Sage Journals: Discover world-class research

Abstract

Introduction:

The renin angiotensin system (RAS) is closely related to the cardiovascular system, body fluid regulation and homeostasis.

Materials and methods:

Despite common therapeutic methods, stem cell/progenitor cell therapy is daily increasing as a term of regenerative medicine. RAS and its pharmacological inhibitors are not only involved in physiological and pathological aspects of the cardiovascular system, but also affect the different stages of stem cell proliferation, differentiation and function, via interfering cell signaling pathways.

Results:

This study reviews the new role of RAS, in particular Ang II distinct from other common roles, by considering its regulating impact on the different signaling pathways involved in the cardiac and endothelial tissue, as well as in stem cell transplantation.

Conclusions:

This review focuses on the impact of stem cell therapy on the cardiovascular system, the role of RAS in stem cell differentiation, and the role of RAS inhibition in cardiac stem cell growth and development.

Keywords

Cardiac tissue differentiation endothelial tissue renin angiotensin system review stem cell transplantation

Introduction

The classical renin-angiotensin system (RAS) is a hormonal system which is commonly associated with blood pressure and body fluid homeostasis regulation.¹ Renin is an enzyme produced in the kidney that metabolizes angiotensinogen to angiotensin I (Ang I), which is then converted to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). Ang II, the major effector peptide of the RAS, acts through its receptors, mainly Angiotensin II receptor Type 1 (AT1) and Angiotensin II receptor Type 2 (AT2)²; however, most cardiovascular effects of Ang II are conveyed by the AT1, which not only includes vasoconstriction, vascular cell hypertrophy, hyperplasia and sodium retention. In addition, AT1 receptor stimulation results in reactive oxygen species (ROS) formation, with inflammatory and thrombotic effects.

AT1, as a G protein-coupled receptor, induces tyrosine kinase phosphorylation. This phosphorylation turns on several downstream signals, like Ras/Rho, mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) and translocation of MAPK into the nucleus.³

Aside, Ang II has the potential to activate the Janus kinase and signal transducer, and the activator of transcription (JAK/STAT) signaling pathway, which is associated in part with acute myocardial ischemia. Furthermore, Ang II stimulates early growth-response genes and myocardial hypertrophy. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-β) and insulin-like growth factor 1 (IGF-1) gene expression are all increased, subsequent to Ang II activation.⁴

The stimulation of ROS production occurs through the activation of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase, as a downstream of RAS signaling pathway in different cell types.⁵

A review of the literature indicates that the AT2 receptor exerts opposite effects to those of the AT1 receptor; and it is over-expressed, especially during pathological circumstances in different organs,⁶ by representing protective effects in end organ damage, such as in stroke and in kidney dysfunction.⁷

The stimulation of the AT2 receptor improves cardiac function after myocardial infarction, through anti-inflammatory and anti-oxidant mechanisms, and by more favorable scar remodeling.^8–10 Moreover, AT2 receptor activation inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activity; and subsequently, the synthesis of pro-inflammatory cytokines.¹¹ AT2 receptor agonists may potentially offer beneficial effects, to improve the regenerative potential of stem or progenitor cells that were derived from patients with cardiovascular disease.¹²

The existence of RAS components in different organs and tissues, especially in renal and cardiovascular diseases,¹³ suggests the presence of local RAS in addition to the circulating common RAS.^13–15 Local RAS participates in various cell functions, such as: cell proliferation, cellular organogenesis and pro-inflammatory actions.¹⁶ Angiotensin mRNA, protein and Ang II are detected in the vascular wall, as components of the local RAS.

Ang II increases vascular tone and blood pressure, by binding to its own receptor. Besides, Ang II has inflammatory effects on the vasculature by inducing integrins, adhesion molecules, cytokines and growth mediators through the activation of the transcription factors and ROS formation.¹⁷ The AT1 receptor activation in vessel wall results in ROS formation and in nitric oxide (NO) inactivation, which is accompanied within the endothelial dysfunction.¹⁸ The heart is itself capable of Ang II production, and cardiac myocytes and fibroblasts express the AT1 receptor. Cardiac hypertrophy and fibrosis occur via the activation of the AT1 receptor, but not the AT2 receptor.¹⁹ Ang II uses mediators, such as endothelin and norepinephrine, in cardiomyocyte growth; and it induces cardiac hypertrophy, via the stimulation of ROS formation.²⁰

Cell-based therapies hold the promise to treat degenerative diseases, cancer and repair of damaged organs for which there are currently no or limited therapeutic options.²¹ Recently, increased developments and research in the stem cell field have attempted to increase stem cell therapy efficacy.^22–24 Besides the role of RAS in stem cell differentiation, its role in function and proliferation makes it an attractive research field in regenerative medicine.²⁵ This review attempts to discuss the effects of Ang II in stem cell therapy, particularly in the cardiovascular system.

Stem cell therapy in the cardiovascular system

Despite extensive and modern methods of pharmacological and surgical treatment of cardiovascular disease (CVD), the CVDs are among the leading causes of death in developed countries. Stem cell therapy has been on the frontier in preventing and treating many diseases, including CVDs with a promising future.^26–28

Mesenchymal stem cells (MSC), which are multi-potent cells, are predominantly found in bone marrow and adipose tissue and can differentiate into various cell types, including cardiomyocytes and endothelial cells.²⁹ Because of the simple isolation of MSCs, their highly immune-privileged and angiogenesis-inducing properties, MSCs seem to be appropriate candidates for stem cell therapy.³⁰ MSCs have shown helpful effects in CVDs, including myocardial infarction (MI), arrhythmias, coronary artery disease (CAD) and atherosclerosis.³¹ Moreover, these cells exert paracrine effects such as neoangiogenesis, reducing myocardial fibrosis and remodeling.³² The injection of cell-free medium containing the secreted factors of MSCs has improved myocardial regeneration after MI. Another paracrine effect of MSCs as an effective approach for re-vascularization is the improvement of microvascular remodeling through the decreasing of oxidative stress.³³ These paracrine effects may act via the suppression of the TGF-β/Smad2 signaling pathway; and behave as an anti-remodeling and endothelial function-improving factor in pulmonary hypertension.³⁴ In the rat pulmonary hypertension model, MSCs show superiority regarding the lowering of blood pressure and thus, ventricular overload; hence, MSC transplantation in chronic lung disease with pulmonary hypertension has pointed toward a new therapeutic intervention.³⁵ In atherosclerotic renal artery stenosis of swine, MSCs that were given concomitant with percutaneous trans-luminal renal angioplasty decrease inflammation, fibrinogenesis and vascular remodeling.³⁶ The anti-inflammatory and immunosuppressive effects of MSC transplantation have influenced arteriosclerosis positively.³⁷ MSCs have the ability to recognize inflammation lesions; and Ang II effects the migration and homing of these cells to the site of injury.³⁸ Dysregulation of the RAS subsides the angiogenic therapeutic potential of these cells.³⁹

Embryonic stem cells (ESCs) are another group of pluripotent cells that are able to differentiate into cardiomyocytes and endothelial cells, which have been mentioned as a source of regeneration therapy.⁴⁰ ESC-derived endothelial cells with therapeutic efficacy not only commence angiogenesis, but also improve the functional properties of the heart.^41,42 In vitro studies indicate that human ESC-derived cardiomyocyte proliferation happens through the PI3/Akt signaling pathway.⁴³ RAS modulates the PI3-K/Akt activation; and inhibition of RAS increases Akt phosphorylation,⁴⁴ which may affect the proliferation of ESCs. Another important, noteworthy issue about these cells is their good survival rate after transplantation.⁴⁵

The concept of postnatal vasculogenesis was introduced within the identification of the circulating endothelial progenitor cell (EPC).⁴⁶ EPCs could originate from hematopoietic stem cells (HSCs) or MSCs.^47,48 In addition, the EPCs existing in the adventitial layer of vessels are able to differentiate into adult endothelial cells.⁴⁹ Vascular damage, ischemia and even physical exercise induce the recruitment of circulating EPCs, resulting in neovascularization and restoration of endothelial function.^50,51 Clinical trial studies have shown an improvement of perfusion in the myocardium by EPC transplantation.^52,53 Regarding EPCs mobilization, several mechanisms have previously been suggested. As such, it was noticed that ischemic injuries release angiogenic factors like VEGF, and activate MAPK or the RAS signaling pathways.^25,54

Although stem cell transplantation looks safe, it may possess serious complications, such as increasing the size of the atherosclerotic area. Labeled bone marrow-derived MSCs have been detected after balloon injury in hyperlipidemic rat arteries, leading to negative remodeling and in situ calcification.⁵⁵ Detection of the non-host origin of tumors after stem cell transplantation indicates their tumorigenic potential.⁵⁶ Unwanted differentiation is another risk factor that may occur in regenerative medicine; and it was reported as MSC differentiation into unwanted mesenchymal cell types, such as osteocytes and adipocytes.⁵⁷ Hence, improving the aforementioned remedies and the current knowledge on the mechanism of stem cell therapy should be considered, as well. Table 1 represents the stem cell types that are discussed in this review. The modulation of progenitor cells and the regulation of their differentiation; and the mobilization mechanism of impaired angiogenesis disease, seem quite remarkable. According to the well-known role of Ang II in CVDs and the RAS intervention in the function, the proliferation and differentiation of stem cell/progenitor cells promote our understanding of such processes.

Table 1.

Stem cell types that are most used in the cardiovascular system.

Stem cell type	Origin	function
Mesenchymal stem cell	Bone marrow or adipose tissue	Neoangiogenic
		Anti-remodeling
		Anti-inflammatory
		Anti-oxidative
Embryonic stem cell	Blastocyst stage of an embryo	Angiogenic, improving cardiac function
Endothelial progenitor cell	HSC / MSC origin	Neovascularization, improving myocardial perfusion

HSC: hematopoietic stem cell; MSC: mesenchymal stem cell

The role of RAS in stem cells

Recent research has attempted to improve stem cell functionality, in order to make stem cells promising candidates for tissue transplantation in different kinds of disease or lost/damaged organs. Emerging studies have examined the RAS influence on stem cell growth, proliferation and function.⁵⁸ Ang II receptor stimulation gives rise to the proliferation of various progenitor cells, such as mouse bone marrow-derived stem cells or human cord blood cells. Lowering the effect of the RAS has a close relationship with anemia, via suppression of bone marrow-derived hematopoietic cell production.⁵⁹ The role of Ang II in the differentiation of stem cell/progenitor cells has been proven in many studies.⁶⁰ The existence of AT receptors in differentiated, but not in undifferentiated cells, suggests the idea that Ang II can also regulate stem cells’ differentiation.⁶¹ Besides the paracrine effects of the RAS direct stem cell/progenitor cells to differentiate into special cells such as SMCs or adipocytes.^62,63

Numerous studies have implicated the role of RAS in the regulation of bone marrow-derived stem cells, especially focusing on hematopoiesis and erythropoiesis in an autocrine/paracrine manner.⁶⁴ The mitogenic function of Ang II results in CD34+ hematopoietic progenitor cell proliferation of early erythroid progenitors, through increasing the number of burst-forming units in erythroid colonies.⁶⁵ Also, AT1 receptor activation stimulates erythroblast proliferation and hemangioblast differentiation, while inhibition of the RAS function diminishes erythropoiesis.⁶⁶ Other components of the RAS are also associated. ACE (also known as CD143) marks hematopoietic stem cells in human embryonic, fetal and adult hematopoietic tissues.⁶⁷ In addition, ACE and the RAS directly regulate hemangioblast expansion and differentiation.⁶⁸ The time of exposure to Ang II is, of course, noticeable in determining the RAS effect on stem cell differentiation. Although acute Ang II signaling mediates proliferative effects on SCs positively, long-term treatment with Ang II increases NADPH oxidase activity and thus, elevated ROS production.^59,69 Expression of Ang II receptors in rat hippocampal neural stem cells (NSCs) leads to the proliferation of related stem cells.⁷⁰ As in NSCs, NADPH oxidase-induced superoxide turns on the stem cells’ proliferation.⁷¹ Ang II can also induce inflammatory responses, through stimulation of ROS generation.⁷² Ang II dose-dependently increases the secretion of inflammatory cytokines such as TNF-α, IL- 1β and IL-6 in bone marrow-derived MSCs.⁷³ Furthermore, the local RAS paracrine activity regulates several signaling pathways in the context of homing and recognizing target tissue for stem cell transplantation.⁷⁴

Stem cells that engraft functionality and differentiations, as well as the embryonic stage differentiation of the progenitor cells, are affected by the RAS.⁷⁵ In addition to influencing cellular function and structure in the adult pancreas, local RAS has a major effect on pancreatic stem cells/progenitor cells (PPC) during development.¹ Pancreatic islet RAS regulates PPC differentiation, after transplantation of MSCs, and thereby enables beneficial outcomes to accomplish permanent normal blood glucose levels in patients with Type 1 diabetes.⁷⁶ Pharmacotherapy by means of the RAS may also be helpful in diabetic, atherosclerotic and hypertensive patients, who are associated with EPC dysfunction and impaired skeletal muscle perfusion. Ang II infusion was shown to increase circulating EPCs by impacting bone marrow-derived EPC differentiation.³⁹

The role of RAS in cardiac stem cells

In addition to influencing in different kinds of stem cells, the RAS effect on CV-related stem cell transplantation has largely been investigated regarding the intracellular signaling pathway of Ang II (Figure1). Induced pluripotent stem cells (iPSCs) are a type of cells that are artificially derived from adult differentiated non-pluripotent somatic cells. Despite different origins, these cells resemble ESCs in their growth and gene expression characteristics.⁷⁷ Besides, iPSCs have the ability to express Ang II receptors. Ang II induces the proliferation of pluripotent cells and instigates their differentiation into MSCs.⁶⁶ Ang II can activate the intracellular signaling cascades via anion superoxide production, which leads to the proliferation of stem cells.⁷⁸ Treating pluripotent stem cells with Ang II and Tempol (ROS production inhibitor) suppresses the proliferation of cells and DNA synthesis that indicates a role in the ROS signaling pathway, in Ang II-induced cell proliferation.⁶⁶ The JAK/STAT pathway also possesses a crucial role in stem cell renewal; and its activation causes p38 phosphorylation and eventually, iPSCs differentiation into the target cell.⁷⁹

Figure1.

Ang II signaling pathway through AT1 receptor and the outcomes in stem cells.

The effect of Ang II on ESC differentiation was also investigated.⁸⁰ The AT1 receptor activation stimulates collagen IV protein, which then induces ESC differentiation to SMCs. Collagen IV is one the extracellular matrix proteins having a role in cell adhesion, growth, differentiation and migration.⁸¹ The PI3/Akt pathway, a downstream cascade activated by Ang II, is involved in ESC differentiation by mediating in the upregulation of several transcription factors, such as: egr-1, c-fos/c-jun, Stat91, NFk-B and the Krüppel-like zinc-finger (KLF5/BTEB2).^82–84 Out of all of them, NFk-B is significantly up-regulated in Ang II-treated cells, suggesting that there is NFk-B involvement in ESC differentiation into the SMSc.^1,85

The TGF-β/Smad pathway possesses a fundamental role in the cellular responses to Ang II. Ang II stimulates TGF-β secretion in different tissues, such as fibroblasts and SMCs, that induce interstitial fibrosis in the heart and kidney.⁸⁶ Furthermore, the TGF-β/Smad 3 pathway is responsible for vascular fibrosis and arteriosclerosis.⁸⁷ The autocrine TGF-β/Smad pathway makes the differentiation of adipose tissue-derived MSCs to SMCs. The inactivation of the TGF-β receptor suppresses the expression of SMC markers such as calponin, h-caldesman and alpha-smooth muscle actin (SMA).⁶³ Besides, TGF-β secretion is associated with the MAPK/ERK pathway; and Ang II in this pathway interferes with TGF-β production, thus resulting in the differentiation of MSCs to SMCs.⁸⁸

As was previously mentioned, MSC transplantation has great importance, along with its various paracrine effects on CVD improvement.^89,90 The supportive effects of vascular endothelial growth factor (VEGF) have been identified in the migration, invasion of extracellular matrix, proliferation and survival of MSCs; and they contribute to MSCs’ paracrine effects;^88,91,92 hence, all pathways increasing VEGF will arise the function of MSCs. Ang II enhances VEGF mRNA and protein expression in MSCs,⁹³ which contributes to the Akt signaling pathway. Ang II is itself associated with Akt signaling pathway activation.^94,95 Pretreatment of MSCs with the Akt inhibitor LY292002 decreases Ang II-induced VEGF expression. Therefore, local Ang II, as a cytokine, may enhance VEGF production in MSC grafts and upgrade the transplantation efficacy.

The role of vascular endothelium in CVD is well-known, but adult endothelial cells have limited regeneration capacity. EPCs are responsible for consistent recovery of endothelium after injury and participate in angiogenesis.⁹⁶ CVDs are related to both the decrease of EPC mobilization and the number of EPCs present in the injured site. Regarding the pathobiology of CVDs, the role of RAS is proved to be effective in EPC function.⁹⁷ The angiogenic function of Ang II stimulates recruitment of EPCs to ischemic regions and starts vascularization, through VEGF-induced endothelial nitric oxide synthase (eNOS).⁹⁸ Moreover, Ang II induces EPC proliferation via a VEGF-mediated signaling pathway.⁹⁹ The formation of NADPH and ROS constitute the stimulatory effects of Ang II on EPCs, which is necessary for normal EPC physiological function, but causes cell senescence in the long term.¹⁰⁰ The main mechanisms of cell senescence are related to the oxidative stress induction and ROS/pyroxynitrite in long-term exposure to the Ang II in EPCs.¹⁰¹ Acute high-dose exposure to Ang II, similar to chronic exposure, also negatively affects EPCs; as in the hind limb ischemic rat model (Ang II infusion decreases the EPC cell population and its angiogenic function).¹⁰²

The role of RAS inhibition in cardiac stem cells

The excess RAS generation is detected in CVDs such as heart failure, myocardial infarction, hypertension and atherosclerosis.¹⁰³ The RAS inhibitors, including ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), have been widely studied in CVDs beyond their impact in lowering the blood pressure.¹⁰⁴ In spite of the increased use of stem cell therapy in regenerative medicine, these cells’ engraftment, improvements and the evaluation of their functional properties are insufficient in clinical trials/animal models^105,106; hence, clarifying the mechanisms that elevate the graft efficacy seems important.

Some researchers evaluated the impact of RAS inhibitors on stem cell therapy in the cardiovascular system.¹⁰⁷ MSCs express both AT1 and AT2 receptors. Ang II induces VEGF secretion in MSCs through phosphorylation of Ser473Akt, which are transplanted into the gastronomies muscle and thus, increases blood flow. Valsartan, an ARB, inhibits VEGF release; and therefore, angiogenesis in vivo.¹⁰⁸ The IGF-1secreted from stem cells has a close relationship with the RAS and down-regulate the local RAS through the attenuation of the p53 gene.¹⁰⁹ The IGF-1 has an anti-apoptotic effect on cardiomyocytes in ischemic heart disease and also enhances differentiation and survival of stem cells after transplantation.¹¹⁰ In acute MI in cardiomyocytes, ACEIs upregulate the IGF-1 receptors; thus, the concurrent use of perindopril in bone marrow stem cell transplantation increases the paracrine effects of the IGF-1, which abolishes apoptosis through increased Bcl2 expression and improves cardiac function.¹¹¹ Also, pre-treatment of MSCs with ARBs before transplantation increases their trans-differentiation efficacy and also improves the systolic function of the heart.¹¹²

EPCs are up-regulated during acute ischemia, while they are down-regulated in atherosclerosis, stable coronary artery disease and Type 2 diabetes mellitus. As mentioned above, Ang II is effective in the recruitment of EPCs to ischemic regions.^113,114 The stimulation of the proliferation in circulating EPCs and increasing of their population is a new strategy for prevention and treatment of ischemic heart disease. The initial observations, linked to the ARBs’ role in increasing the EPC population, were reported in Type 2 diabetes mellitus patients whom were treated with olmesartan and irbesartan for 2 weeks.¹¹⁵ In addition, irbesartan in hyperchlostrelomic hamsters elevates the number of circulating EPCs and suppresses plaque formation in atherosclerosis, via inhibition of pro-inflammatory factors.¹¹⁶ A decrease in the number of circulating EPCs is one of the reasons for impaired vasculogenesis and reduced blood flow in Type 2 diabetes mellitus patients.¹¹⁷ In long-term use and an escalation of dose, Valsartan increases circulating EPCs in diabetic patients with asymptomatic coronary artery disease.¹¹⁸ The exact underlying mechanism remains to be elucidated, but suppression of oxidative stress might be one possible hypothesis of valsartan function.¹¹⁹

ARBs also increase the EPC population in hypertensive patients. Cell redox balance is a regulator of self-renewal and differentiation in stem cell/progenitor cells, and antioxidants help preserving their function.¹²⁰

ARBs can improve EPC dysfunction by reducing oxidative stress.¹²¹ In clinical studies ramipiril, an ACEI, increases the number and the function of the EPCs without affecting blood pressure.¹²² Telmisartan has a beneficial effect on the number of circulating EPC in normotensive patients with coronary artery disease.¹²³ The oxidative stress also diminishes the half-life of circulating EPCs, thus blocking of the ROS by ARBs extends their life.¹²⁴ The local RAS is associated with oxidative stress in the cardiovascular system. In precursor cells, Ang II and its oxidative stress signaling cause cardiac cell death.¹²⁵ Besides, inhibiting the NADPH oxidase via ARBs and their antioxidant effects generate vasoprotective effects.¹²⁴ Candesartan increases EPC colonies in colony-forming unit assays, in spontaneously hypertensive rats. Down-regulation of NADPH oxidase and the reduction of the thiobarbitoric acid-reactive substance (TRABS) score demonstrate the candesartan effects through its antioxidant mechanism.¹²⁶ Lowering blood pressure in 90% of hypertensive patients with ARBs without any connection to plasma renin function indicates the pathogenesis of primary hypertension, which is related to tissue angiotensin.¹²⁷ Losartan increases both the number and the migration of the EPCs that are augmented in pretreatment with tempol, suggesting the antioxidant pathway of the drug.¹²⁷

Cell-derived micro-particles (MPs) have been a matter of interest, due to their essential role in vascular homeostasis in various physiologic and pathologic processes. Platelets, blood cells and endothelium are the MP source.¹²⁸ MPs are the atherosclerosis markers and they increase during the disease, compared to EPCs. Irbesartan not only performs beneficial effects on the number, function, engraftment efficacy and the survival of EPCs; but also decreases MPs.¹²⁹

Some ARBs, such as telmisartan, are peroxisome proliferator-activated receptor gamma (PPAR-γ) ligands.¹³⁰ Upon finding that thiazolidonediones (PPAR-γ agonists) reduce vascular inflammation and stimulate neo-vasculogenesis in the cerebral ischemic model, it is possible that ARBs that are PPAR-γ agonists could be effective in this context. Telmisartan induces adiponectin secretion via a PPAR-γ activation mechanism.^131,132 Adiponectin, an anti-atherogenic adipo-cytokine, induces angiogenesis in different in vivo and in vitro models.¹³³ Besides that, telmisartan increases the proliferation of EPCs derived from blood by the PI3/Akt signaling pathway. Findings in a Β-gal-staining study indicate that telmisartan in high doses can upregulate Akt-mediated p53 that is involved in cell senescence.¹³¹

Conclusion

In summary, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in CVD patients. In order to improve the efficiency of regenerative medicine, researchers investigated the effect of the modulation of various cell-signaling pathways, including the RAS. Effects of Ang II in stem cell proliferation and differentiation have been documented in the literature. The presence of the RAS components in progenitor cells and the cardiovascular tissue may regulate growth and development; and thus, may contribute to preparation of cardiovascular progenitor cells for clinical transplantation. Pharmacotherapy by means of ARBs or ACEIs that affect cell-signaling mechanisms is a potential therapeutic intervention.

Footnotes

Acknowledgements

The moral support of the Faculty of Pharmacy, Tabriz University of Medical Sciences in Tabriz, Iran is gratefully acknowledged.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Notes

References

Wang

Leung

. The role of renin-angiotensin system in cellular differentiation: Implications in pancreatic islet cell development and islet transplantation. Molec Cell Endocrinol 2013; 381: 261–271.

Bader

. Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Ann Rev Pharmacol Toxicol 2010; 50: 439–465.

Akazawa

Yano

Yabumoto

. Angiotensin II Type 1 and Type 2 receptor-induced cell signaling. Curr Pharmaceut Design 2013; 19: 2988–2995.

Becher

Endtmann

Tiyerili

. Endothelial damage and regeneration: The role of the renin-angiotensin-aldosterone system. Curr Hypertens Rep 2011; 13: 86–92.

Welch

. Angiotensin II-dependent superoxide: Effects on hypertension and vascular dysfunction. Hypertension 2008; 52: 51–56.

Schmieder

Hilgers

Schlaich

. Renin-angiotensin system and cardiovascular risk. Lancet 2007; 369: 1208–1219.

Steckelings

Larhed

Hallberg

. Non-peptide AT2-receptor agonists. Curr Opin Pharmacol 2011; 11: 187–192.

Kaschina

Grzesiak

. Angiotensin II Type 2 receptor stimulation: A novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation 2008; 118: 2523–2532.

Hardwick

Ryan

Powers

. Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus. Am J Physiol-Regulat Integr Compar Physiol 2015: ajpregu.00004.2015.

10.

Skorska

Haehling

Ludwig

. The CD4+ AT2R+ T-cell subpopulation improves post-infarction remodelling and restores cardiac function. J Cell Molec Med 2015; 19: 1975–1985.

11.

Rompe

Artuc

Hallberg

. Direct angiotensin II Type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor κB. Hypertension 2010; 55: 924–931.

12.

Ludwig

Steinhoff

. The regenerative potential of angiotensin AT2 receptor in cardiac repair. Canad J Physiol Pharmacol 2012; 90: 287–293.

13.

Campbell

. Clinical relevance of local renin angiotensin systems. Frontiers Endocrinol 2014; 5: 113.

14.

Wright

Harding

. The brain renin–angiotensin system: A diversity of functions and implications for CNS diseases. Pflugers Arch Eur J Physiol 2013; 465: 133–151.

15.

Skipworth

JRA

Szabadkai

Olde Damink

SWM

. Review article: Pancreatic renin-angiotensin systems in health and disease. Aliment Pharmacol Therapeut 2011; 34: 840–852.

16.

De Mello

Frohlich

. On the local cardiac renin angiotensin system. Basic and clinical implications. Peptides 2011; 32: 1774–1779.

17.

Marchesi

Paradis

Schiffrin

. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci 2008; 29: 367–374.

18.

Paravicini

Touyz

. NADPH oxidases, reactive oxygen species and hypertension: Clinical implications and therapeutic possibilities. Diabet Care 2008; 31: S170–180.

19.

Lévy

. Can angiotensin II Type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation 2004; 109: 8–13.

20.

Yan

Schuldt

Price

. Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Am J Physiol Heart Circ Physiol 2008; 294: 1274–1281.

21.

Trounson

Thakar

Lomax

. Clinical trials for stem cell therapies. Brit Med C Med 2011; 9: 52.

22.

Chou

Lin

Kuo

. Mesenchymal stem cell insights: Prospects in cardiovascular therapy. Cell Transplant 2014; 23: 513–529.

23.

Qayyum

Mathiasen

Kastrup

. Stem cell therapy to treat heart ischaemia: Implications for diabetes cardiovascular complications. Curr Diab Rep 2014; 14: 554.

24.

Willerson

. Stem cell therapy for cardiovascular diseases: A progressive journey. Curr Op Cardiol 2015; 30: 205–212.

25.

Durik

Seva Pessoa

Roks

. The renin-angiotensin system, bone marrow and progenitor cells. Clin Sci 2012; 123: 205–223.

26.

Rosamond

Flegal

Friday

. Heart disease and stroke statistics. 2007 Update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69–171.

27.

Kim

Shapiro

Flynn

. The clinical application of mesenchymal stem cells and cardiac stem cells as a therapy for cardiovascular disease. Pharmacol Therapeut 2015; 151: 8–15.

28.

Wegener

Bader

Giri

. How to mend a broken heart: Adult and induced pluripotent stem cell therapy for heart repair and regeneration. Drug Discov Today 2015; 20: 667–685.

29.

Trivedi

Tray

Nguyen

. Mesenchymal stem cell therapy for treatment of cardiovascular disease: Helping people sooner or later. Stem Cell Dev 2010; 19: 1109–1120.

30.

Jiang

Kh Haider

Ahmed

RPH

. Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium. J Mol Cell Cardiol 2008; 44: 582–596.

31.

Lopes

Fiarresga

Silva Cunha

. [Mesenchymal stem cell therapy in heart disease]. Rev Port Cardiol 2013; 32: 43–47.

32.

Choi

Y-H

Kurtz

Stamm

. Mesenchymal stem cells for cardiac cell therapy. Hum Gene Ther 2010; 22: 3–17.

33.

Eirin

Zhu

X-Y

Krier

. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cell 2012; 30: 1030–1041.

34.

Xie

Niu

. Mesenchymal stem cells attenuate vascular remodeling in monocrotaline-induced pulmonary hypertension rats. J Huazhong Univ Sci Technol 2012; 32: 810–817.

35.

Hansmann

Fernandez-Gonzalez

Aslam

. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2012; 2: 170–181.

36.

Ebrahimi

Eirin

. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis. PloS One 2013; 8: e67474.

37.

Chamberlain

Smith

Rainger

. Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: Effects of chemokines and shear. PloS One 2011; 6: e25663.

38.

Resende

Stodola

Greene

. Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis after electrical stimulation. FASEB J 2009; 23: 1030.10.

39.

de Resende

Stodola

Greene

. Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis. Physiolog genomics 2010; 42: 437–444.

40.

Mummery

Zhang

. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: A methods overview. Circ Res 2012; 111: 344–358.

41.

Sheikh

. Differentiation, survival and function of embryonic stem cell-derived endothelial cells for ischemic heart disease. Circulation 2007; 116: I46–54.

42.

Lundy

Zhu

Regnier

. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Dev 2013; 22: 1991–2002.

43.

McDevitt

Laflamme

Murry

. Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. J Mol Cell Cardiol 2005; 39: 865–873.

44.

Cheng

Hsiao

. Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT1 and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii. Br J Pharmacol 2012; 166: 2024–2035.

45.

Van Laake

Passier

Monshouwer-Kloots

. Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res 2007; 1: 9–24.

46.

Asahara

Kawamoto

Masuda

. Concise review: Circulating endothelial progenitor cells for vascular medicine. Stem Cell 2011; 29: 1650–1655.

47.

Sata

Saiura

Kunisato

. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002; 8: 403–409.

48.

Reyes

Dudek

Jahagirdar

. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002; 109: 337–346.

49.

Richardson

Yoder

. Endothelial progenitor cells: Quo vadis? J Mol Cell Cardiol 2011; 50: 266–272.

50.

Corselli

Chen

Sun

. The tunica adventitia of human arteries and veins as a source of mesenchymal stem cells. Stem Cell Dev 2012; 21: 1299–1308.

51.

Lam

C-F

Roan

J-N

Lee

C-H

. Transplantation of endothelial progenitor cells improves pulmonary endothelial function and gas exchange in rabbits with endotoxin-induced acute lung injury. Anesthes Analges 2011; 112.

52.

Traverse

Henry

Ellis

. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: The latetime randomized trial. J Am Med Ass 2011; 306: 2110–2119.

53.

Leistner

Fischer-Rasokat

Honold

. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): Final 5-year results suggest long-term safety and efficacy. Clin Res Cardiol 2011; 100: 925–934.

54.

Jiang

Liang

Liu

. Palmitic acid promotes endothelial progenitor cell apoptosis via p38 and JNK mitogen-activated protein kinase pathways. Atherosclerosis 2010; 210: 71–77.

55.

Liao

Chen

. Transfer of bone-marrow-derived mesenchymal stem cells influences vascular remodeling and calcification after balloon injury in hyperlipidemic rats. J Biomed Biotechnol 2012; 2012: 165296.

56.

Amariglio

Hirshberg

Scheithauer

. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 2009; 6: e1000029.

57.

Breitbach

Bostani

Roell

. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007; 110: 1362–1369.

58.

Becher

Endtmann

Tiyerili

. Endothelial damage and regeneration: The role of the renin-angiotensin-aldosterone system. Curr Hypertens Rep 2011; 13: 86–92.

59.

Endtmann

Ebrahimian

Czech

. Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration. Hypertension 2011; 58: 394–403.

60.

Matsushita

Okamoto

. Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension 2006; 48: 1095–1102.

61.

Huang

Toselli

. Angiotensin II Type 1 and bradykinin B2 receptors expressed in early stage epithelial cells derived from human embryonic stem cells. J Cellul Physiol 2007; 211: 816–825.

62.

Jia

Yan

. Angiotensin II promotes cardiac differentiation of embryonic stem cells via angiotensin Type 1 receptor. Differentiation 2013; 86: 23–29.

63.

Kim

Jeon

Kim

. Angiotensin II-induced differentiation of adipose tissue-derived mesenchymal stem cells to smooth muscle-like cells. Int J Biochem Cell Biol 2008; 40: 2482–2491.

64.

Kim

Cogle

Zingler

. Angiotensin II-induced hypertension has significant effects on proliferation, differentiation and engraftment efficacy of hematopoietic stem cell. Hypertension 2014; 64: A20.

65.

Mrug

Stopka

Julian

. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997; 100: 2310.

66.

Ishizuka

Goshima

Ozawa

. Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells. Biochem Biophys Res Commu 2012; 420: 148–155.

67.

Jokubaitis

Sinka

Driessen

. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal and adult hematopoietic tissues. Blood 2008; 111: 4055–4063.

68.

Zambidis

Park

. Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells. Blood 2008; 112: 3601–3614.

69.

Durik

Pessoa

Roks

. The renin-angiotensin system, bone marrow and progenitor cells. Clin Sci 2012; 123: 205–223.

70.

Chao

Yang

Buch

. Angiotensin II increased neuronal stem cell proliferation: Role of AT2R. PloS One 2013; 8: e63488.

71.

Topchiy

Panzhinskiy

Griffin

WST

. Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation. Develop Neurosci 2013; 35: 293–305.

72.

Holmström

Finkel

. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nature Rev Molec Cell Biol 2014; 15: 411–421.

73.

Zhang

Wang

. Aspirin attenuates angiotensin II-induced inflammation in bone marrow mesenchymal stem cells via the inhibition of ERK1/2 and NF-kappaB activation. Biomed Rep 2013; 1: 930–934.

74.

Öztürk

Güven

Haznedaroglu

. How hematopoietic stem cells know and act in cardiac microenvironment for stem cell plasticity? Impact of local renin-angiotensin systems. Med Hypothes 2004; 63: 866–874.

75.

Xue

Zhang

. Angiotensin II promotes differentiation of mouse c-kit-positive cardiac stem cells into pacemaker-like cells. Molec Med Rep 2015; 11: 3249–3258.

76.

Leung

Liang

. Angiotensin II Type 2 receptor is critical for the development of human fetal pancreatic progenitor cells into islet-like cell clusters and their potential for transplantation. Stem Cell 2012; 30: 525–536.

77.

Thomson

. Pluripotent stem cell lines. Genes Develop 2008; 22: 1987–1997.

78.

Chan

Jiang

Peshavariya

. Regulation of cell proliferation by NADPH oxidase-mediated signaling: Potential roles in tissue repair, regenerative medicine and tissue engineering. Pharmacol Therapeut 2009; 122: 97–108.

79.

Kristensen

Kalisz

Nielsen

. Cytokine signalling in embryonic stem cells. APMIS 2005; 113: 756–772.

80.

Matsushita

Okamoto

. Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension 2006; 48: 1095–1102.

81.

Xiao

Zeng

Zhang

. Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury. Arterioscler Thromb Vasc Biol 2006; 26: 2244–2251.

82.

Shindo

Manabe

Fukushima

. Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nature Med 2002; 8: 856–863.

83.

Bhat

Thekkumkara

Thomas

. Angiotensin II stimulates sis-inducing factor-like DNA binding activity. Evidence that the AT1A receptor activates transcription factor-Stat91 and/or a related protein. J Biolog Chem 1994; 269: 31443–31449.

84.

Nagai

Izumi-Nagai

Oike

. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II Type 1 receptor or its downstream nuclear factor-κB pathway. Inves Ophthalmol Visual Sci 2007; 48: 4342–4350.

85.

Huang

Wang

Yang

. Angiotensin II promotes poly(ADP-ribosyl)ation of c-Jun/c-Fos in cardiac fibroblasts. J Mol Cell Cardiol 2009; 46: 25–32.

86.

Yurovsky

Gerzanich

Ivanova

. Autocrine TGF-β1 mediates angiotensin II-induced proliferative response of cerebral vessels in vivo. Am J Hypertens 2007; 20: 950–956.

87.

Wang

Huang

Canlas

. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res 2006; 98: 1032–1039.

88.

Jeon

Moon

Lee

. Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-beta-dependent mechanism. J Cell Sci 2006; 119: 4994–5005.

89.

Imanishi

Saito

Komoda

. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. J Mol Cell Cardiol 2008; 44: 662–671.

90.

Williams

Trachtenberg

Velazquez

. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: Functional recovery and reverse remodeling. Circ Res 2011; 108: 792–796.

91.

Uemura

Dai

. In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol 2007; 42: 441–448.

92.

Potapova

Gaudette

Brink

. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cell 2007; 25: 1761–1768.

93.

Shi

R-Z

Wang

J-C

Huang

S-H

. Angiotensin II induces vascular endothelial growth factor synthesis in mesenchymal stem cells. Exp Cell Res 2009; 315: 10–15.

94.

Slomiany

Black

Kibbey

. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun 2006; 342: 851–858.

95.

Carvalheira

Calegari

Zecchin

. The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: Implications for insulin resistance. Endocrinology 2003; 144: 5604–5614.

96.

Lee

PSS

Poh

. Endothelial progenitor cells in cardiovascular diseases. World J Stem Cell 2014; 6: 355.

97.

Shantsila

Watson

Lip

GYH

. Endothelial progenitor cells in cardiovascular disorders. J Am College Cardiol 2007; 49: 741–752.

98.

Hiasa

Ishibashi

Ohtani

. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: Next-generation chemokine therapy for therapeutic neovascularization. Circulation 2004; 109: 2454–2461.

99.

Imanishi

Hano

Nishio

. Angiotensin II potentiates vascular endothelial growth factor-induced proliferation and network formation of endothelial progenitor cells. Hypertension Res 2004; 27: 101–108.

100.

Imanishi

Hano

Nishio

. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens 2005; 23: 97–104.

101.

Kobayashi

Imanishi

Akasaka

. Endothelial progenitor cell differentiation and senescence in an angiotensin II-infusion rat model. Hypertens Res 2006; 29: 449–455.

102.

You

Cochain

Loinard

. Combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide activate postnatal vasculogenesis in spontaneously hypertensive rats. J Pharmacol Exp Ther 2008; 325: 766–773.

103.

Haznedaroglu

Beyazit

. Pathobiological aspects of the local bone marrow renin-angiotensin system: A review. J Renin Angiotensin Aldosterone Syst 2010; 11: 205–213.

104.

Taylor

Siragy

Nesbitt

. Angiotensin receptor blockers: Pharmacology, efficacy and safety. J Clin Hypertens 2011; 13: 677–686.

105.

Cleland

JGF

Freemantle

Coletta

. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE and PROACTIVE. Eur J Heart Failure 2006; 8: 105–110.

106.

Abdel-Latif

Bolli

Tleyjeh

. Adult bone marrow-derived cells for cardiac repair: A systematic review and meta-analysis. Arch Int Med 2007; 167: 989–997.

107.

Ebrahimian

Tamarat

Clergue

. Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in Type 1 diabetic mice. Arterioscler Thromb Vasc Biol 2005; 25: 65–70.

108.

Cheng

C-I

Hsiao

C-C

S-C

. Valsartan impairs angiogenesis of mesenchymal stem cells through Akt pathway. Int J Cardiol 2013; 167: 2765–2774.

109.

Huynh

McMullen

Julius

. Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes 2010; 59: 1512–1520.

110.

O’Sullivan

Leblond

Kelly

. Potent long-term cardioprotective effects of single low-dose insulin-like growth factor-1 treatment postmyocardial infarction. Circulat Cardiovasc Intervent 2011; 4: 327–335.

111.

Huang

Y-L

Kuang

Y-Z

. Bone marrow stromal cell transplantation combined with angiotensin-converting enzyme inhibitor treatment in rat with acute myocardial infarction and the role of insulin-like growth factor-1. Cytotherapy 2012; 14: 563–569.

112.

Numasawa

Kimura

Miyoshi

. Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis. Stem Cell 2011; 29: 1405–1414.

113.

Krankel

Adams

Linke

. Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 2005; 25: 698–703.

114.

Lobo

Patil

Phatak

. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy Rev 2010; 4: 118.

115.

Bahlmann

De Groot

Mueller

. Stimulation of endothelial progenitor cells: A new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005; 45: 526–529.

116.

Georgescu

Alexandru

Andrei

. Circulating microparticles and endothelial progenitor cells in atherosclerosis: Pharmacological effects of irbesartan. J Thrombos Haemostas 2012; 10: 680–691.

117.

Hernandez

Gong

Chen

. Characterization of circulating and endothelial progenitor cells in patients with extreme-duration Type 1 diabetes. Diabet Care 2014; 37: 2193–2201.

118.

Berezin

Kremzer

Martovitskaya

. The effect of angiotensin-2 receptor blocker valsartan on circulating level of endothelial progenitor cells in diabetic patients with asymptomatic coronary artery disease. Diabet Metabol Syndr Clin Res Rev 2015; 9: 305–309.

119.

Zhao

Wang

Siu

. Myocardial dysfunction in patients with Type 2 diabetes mellitus: Role of endothelial progenitor cells and oxidative stress. Cardiovasc Diabetol 2012; 11: 147.

120.

Noble

Smith

Power

. Redox state as a central modulator of precursor cell function. Ann NY Acad Sci 2003; 991: 251–271.

121.

Fukuda

Sata

. The renin-angiotensin system: A potential modulator of endothelial progenitor cells. Hypertens Res 2007; 30: 1017–1018.

122.

Min

Zhu

Xiang

. Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drug Ther 2004; 18: 203–209.

123.

Pelliccia

Pasceri

Cianfrocca

. Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: A randomized, double-blind, placebo-controlled study. Atherosclerosis 2010; 210: 510–515.

124.

Dernbach

Urbich

Brandes

. Antioxidative stress-associated genes in circulating progenitor cells: Evidence for enhanced resistance against oxidative stress. Blood 2004; 104: 3591–3597.

125.

Sanada

Kitakaze

Node

. Differential subcellular actions of ACE inhibitors and AT1 receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats. Hypertension 2001; 38: 404–411.

126.

Fukuda

Yao

. Effects of an ARB on endothelial progenitor cell function and cardiovascular oxidation in hypertension. Am J Hypertens 2008; 21: 72–77.

127.

Yao

Fukuda

Matsumoto

. Losartan improves the impaired function of endothelial progenitor cells in hypertension via an antioxidant effect. Hypertens Res 2007; 30: 1119–1128.

128.

Burnier

Fontana

Kwak

. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009; 101: 439–451.

129.

Georgescu

Alexandru

Nemecz

. Irbesartan administration therapeutically influences circulating endothelial progenitor cell and microparticle mobilization by involvement of pro-inflammatory cytokines. Eur J Pharmacol 2013; 711: 27–35.

130.

Kurtz

. Treating the metabolic syndrome: Telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol 2005; 42: S9–16.

131.

Chu

Lee

S-T

Koo

J-S

. Peroxisome proliferator-activated receptor-γ-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia. Brain Res 2006; 1093: 208–218.

132.

Clasen

Schupp

Foryst-Ludwig

. PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension 2005; 46: 137–143.

133.

Ouchi

Kobayashi

Kihara

. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004; 279: 1304–1309.

Role of angiotensin II in stem cell therapy of cardiac disease

Abstract

Introduction:

Materials and methods:

Results:

Conclusions:

Keywords

Introduction

Stem cell therapy in the cardiovascular system

The role of RAS in stem cells

The role of RAS in cardiac stem cells

The role of RAS inhibition in cardiac stem cells

Conclusion

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

Notes

References