Sage Journals: Discover world-class research

Abstract

Despite the recent progress in research and therapy, cardiovascular diseases are still the most common cause of death worldwide, thus new approaches are still needed. The aim of this review is to highlight the cardioprotective potential of urocortins and corticotropin-releasing hormone (CRH) and their signaling. It has been documented that urocortins and CRH reduce ischemic and reperfusion (I/R) injury, prevent reperfusion ventricular tachycardia and fibrillation, and improve cardiac contractility during reperfusion. Urocortin-induced increase in cardiac tolerance to I/R depends mainly on the activation of corticotropin-releasing hormone receptor-2 (CRHR2) and its downstream pathways including tyrosine kinase Src, protein kinase A and C (PKA, PKCε) and extracellular signal-regulated kinase (ERK1/2). It was discussed the possibility of the involvement of interleukin-6, Janus kinase-2 and signal transducer and activator of transcription 3 (STAT3) and microRNAs in the cardioprotective effect of urocortins. Additionally, phospholipase-A2 inhibition, mitochondrial permeability transition pore (MPT-pore) blockade and suppression of apoptosis are involved in urocortin-elicited cardioprotection. Chronic administration of urocortin-2 prevents the development of postinfarction cardiac remodeling. Urocortin possesses vasoprotective and vasodilator effect; the former is mediated by PKC activation and prevents an impairment of endothelium-dependent coronary vasodilation after I/R in the isolated heart, while the latter includes both cAMP and cGMP signaling and its downstream targets. As CRHR2 is expressed by both cardiomyocytes and vascular endothelial cells. Urocortins mediate both endothelium-dependent and -independent relaxation of coronary arteries.

Keywords

corticotropin-releasing hormone urocortins heart ischemia reperfusion

Introduction

Urocortins and corticotropin-releasing hormone (CRH) belong to the family of CRH. In 1955, two groups of researchers received convincing evidence of the existence of CRH, also called corticotropin-releasing factor (CRF).^1,2 In 1981, a team of researchers led by Professor W. Vale isolated 90 µg of CRF from the hypothalamus of sheep, elucidated the molecular structure of CRH.^3,4 It turned out to be this peptide consisting of 41 amino acid residues.³ In 1995, a peptide consisting of 40 amino acid residues was isolated from the rat midbrain, which the authors named urocortin.⁵ This urocortin possessed 45% and 60% homology with CRH and urotensin, respectively, and is now recognized as urocortin-1. Later, urocortin-2 was discovered as a 38-amino acid peptide that shows about 34%, homology with rat and human CRH and also it has similarities with urocortin-1 (43%) and urocortin-3 (37%-40%).^6,7 Urocortin-3 is composed of 38 amino acids and has approximately 20%-40% similarity to CRH and urocortin-1. Urocortin-2 and urocortin-3 have a sequence similarity of up to 40%.⁷

The purpose of this article is an analysis the cardioprotective properties of urocortins and corticotropin-releasing hormone and signaling mechanism of their cardiovascular effects.

Localization of CRH and Urocortins in Organs and Tissues

CRH is found in the paraventricular nucleus (PVN) of the hypothalamus, amygdala, the stria terminalis nucleus, and other structures of the brain.⁸ At the periphery, CRF is presented in the stomach wall, the placenta, adrenal glands.⁸ Urocortin-1 is predominantly expressed in the Edinger Westphal nucleus, the hypothalamus and in the supraoptic nuclei of the brain.^8,9 At the periphery, urocortin-1 is found in the intestine, liver, cardiomyocytes, thymus, skin, spleen and immune cells.^8,9 Urocortin-2 is expressed in the hypothalamus, brainstem and spinal cord⁸ and at the periphery, it is found in the gastrointestinal tract, the heart, coronary arteries, thymus, blood cells and adrenal glands.^8,9 Urocortin-3 is found in the hypothalamus and amygdala, the intestine and pancreas.⁸ All 3 urocortins have been detected in the heart.⁹ Urocortin mRNA was found in spleen, thymus, stomach, the small intestine, kidney, testes, the heart and liver.¹⁰ The highest level of urocortin mRNA expression was detected in thymus.¹⁰ However, later on RT-PCR revealed the presence of urocortin-2 mRNA in adrenal glands as well.¹¹

Urocortins appear to be peptides resistant to enzymatic hydrolysis. According to Patel et al, urocortin-1 half-life is 2.9 h (alpha phase) and 8.3 h (beta phase) in sheep.¹² In other peptides half-life is significantly shorter: for urocortin-2 it is 15.7 min; for urocortin-3, it is 4.4 min. All urocortins caused an increase in cardiac output and tachycardia in naïve sheep.¹² Urocortin-1 hemodynamic effects persisted for more than 6 h, in urocortin-2 and urocortin-3 for 1 h.¹² A plasma urocortin-1 half-life is 54 min in human.¹³ Urocortin crosses the blood-brain barrier (BBB) in rats with intracerebral hemorrhage and has a neuroprotective effect.¹⁴ However, in ischemic and hemorrhagic stroke the integrity of the BBB is impaired¹⁵ and thus it was unclear whether urocortin can penetrate the BBB in healthy people and animals. Since it was demonstrated that urocortin can penetrate into the endothelial cells of cerebral microvessels in vitro, this cannot be ruled out.¹⁶ Urocortin-1 is an autocrine and/or paracrine modulator of the local immune response.⁹ Urocortin-1 can induce secretion of proinflammatory cytokines (interleukin-1β, interleukin-6).⁹ It should be note that most authors do not indicate the exact name of urocortin in their articles.

CRH Receptors

CRH binds to 2 CRH-receptor isoforms, CRHR1 and CRHR2, which are G-protein coupled receptors.^9,17 CRHR1 is mainly expressed in the brain, while CRHR2 is expressed in peripheral organs, and particularly in the heart.¹⁸ It has been shown that urocortins and both CRHR isoforms are expressed in cardiomyocytes.¹⁹ Although the amino acid sequence of CRHR1 is 70% identical to CRHR2, their receptors show selectivity for both ligands. CRHR1 and CRHR2 are encoded by the genes Crhr1 and Crhr2, respectively. Both have 3 splice variants.¹⁷ CRH is the predominant CRHR1 agonist. Urocortin-1 has the equal affinity to both CRHR1 and CRHR2. Urocortin-2 is the selective CRHR2 agonist and similarly, urocortin-3 is the predominant agonist of CRHR2 (Figure 1).²⁰ CRHR1 and CRHR2, like adenosine receptors, interact with various G-proteins: Gs, Gq, Gi.¹⁷ CRHR1 is coupled to following G proteins: Gαs, Gαo, Gαq/11 and Gαi1/2.²¹

Figure 1.

Interaction corticotropin-releasing factor (CRF) and urocortins (Ucn) with corticotropin-releasing hormone receptors (CRHR).

Stimulation of CRHRs contributes to the activation of both cAMP and cGMP synthesis, to an increase in activity of protein kinase A (PKA), Epac (exchange protein activated by cAMP), ERK (extracellular signal-regulated kinase), and protein kinase C (PKC).²¹ It was found that urocortin-2 increases NO production in cardiomyocytes by stimulating endothelial NO-synthase. In addition, urocortin also activates PKA, phosphatidylinositol 3-kinase (PI3 K), Akt kinase and ERK.²² Urocortin increased the cAMP and cGMP level in cardiomyocytes (Figure 2).²²

These data explain the many effects that CRH and urocortins have.

Figure 2.

Intracellular signaling pathway in the development of the cardioprotective effect activation of corticotropin-releasing hormone receptors (CRHR). AC, adenylate cyclase; Akt, protein kinase B; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CRH, corticotropin-releasing hormone; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular regulated kinase; Gα,β,γ, G protein; EPAC, exchange protein activated by cAMP; NO, nitric oxide; PI3K, phosphoinositide-3-kinase; PKA, protein kinase A; PKC, protein kinase C; Src, proto-oncogene, non-receptor tyrosine kinase; Ucn, urocortine.

CRH and Urocortins in Stress

CRH and urocortins play an important role in the regulation of ACTH secretion.²³ Urocortin-1 causes a catecholamine secretion by adrenal glands.⁹ Urocortin-1, CRHR1 and CRHR2 are found in the thyroid gland and are believed to regulate thyroid hormone synthesis.¹⁷ Besides, CRH and urocortins are involved in the regulation of animal behavior.^17,24,25 Immobilization stress (60 min) did not affect the plasma urocortin-2 level in rats.²⁶ However, after a 2-hour immobilization of rats, elevation of the urocortin-2 mRNA level was repeatedly observed in adrenal glands.¹¹ Under periodic immobilization stress (2 h x 6 days), the urocortin-2 mRNA level increased 10-fold. It has been shown that stress causes an increase in the plasma CRH level in rats.²⁷ There is evidence that in the first days of chronic hypoxia plasma CRH concentration is elevated in rats, but on the 15th day of adaptation, its level returns to control values.²⁸ It is possible that CRH and/or urocortin can be involved in the cardioprotective effect of chronic hypoxia or cold adaptation.^29
-31

CRH and Urocortin-Induced Vasodilation

Vascular endothelium expresses both CRHR isoforms,³² which can make a significant contribution to urocortin-induced vasodilation (Figure 3). Urocortins induce vasodilation of renal arteries and, thus, are involved in the regulation of blood pressure at kidney hypertension.⁹ Urocortin-2a and urocortin-3 induced dose-dependent forearm arterial vasodilatation in patients with heart failure or healthy subjects.³³ CRHR2 was found in intramyocardial blood vessels of the human heart and in the medial layer of the internal mammary artery.³⁴ The ability of urocortin to induce vasodilation was demonstrated in rat basilar artery segments precontracted with prostaglandin F2α.³⁵ The relaxant effect of urocortin was eliminated by the selective CRHR2 antagonist astressin 2B.³⁵ Pretreatment with the adenylyl cyclase (AC) inhibitor SQ22536, the non-selective K⁺ channel blocker tetraethylammonium abolished urocortin-induced vasorelaxation.³⁵ The big conductance K⁺ channel blocker (BK_Ca channel) iberiotoxin and small conductance K_Ca ² channel blocker (K_Ca ² SK channel) apamin reduced urocortin-induced vasorelaxation but acted weaker than SQ22536 or tetraethylammonium.³⁵ CRH also induced vasorelaxation but had a much weaker effect than urocortin: CRH-induced vasorelaxation required a 100-fold higher concentration of CRH than urocortin. In rat tail arteries it has been demonstrated that urocortin exhibits a potent, endothelium-independent vasodilator effect mediated via PKA activation.³⁶ However, it was later shown that urocortin induced both, endothelium-dependent and -independent relaxation of the rat left anterior descending coronary artery.³⁷ Maximum vasodilation of the coronary artery is achieved at a concentration of urocortin of 3 nM.³⁷ After endothelial removal, 20 nM is required for maximum vasodilation. Urocortins induce NO secretion by endothelial cells.⁹ The NO-synthase (NOS) inhibitor L-NAME reduced urocortin-induced vasodilation. The selective inhibitor of NO-sensitive guanylyl cyclase (GC) ODQ also decreased the vasodilator effect of urocortin in the rat coronary artery.³⁸ The selective inward-rectifier K⁺ channel blocker tertiapin-Q attenuated urocortin-induced vasodilation, and it was concluded that urocortin-induced endothelium-dependent relaxation appears to be mediated by cGMP-dependent mechanisms which include NOS and inward-rectifier K⁺ channels.³⁷ Later, the same investigators demonstrated that urocortin relaxed the rat coronary artery via activation of Ca²⁺-sensitive K⁺ channels and this effect appears to be mediated through the PKA-dependent intracellular mechanisms.³⁸ Consequently, urocortin-induced endothelium-dependent relaxation of coronary arteries appears to be cGMP- and cAMP-dependent. Urocortin-induced relaxation of rat pulmonary artery was shown to be independent of the presence of endothelium.³⁹ This effect of urocortin is mediated via CRHR2 and PKA, and was independent from NOS. Urocortin reduced phenylephrine-induced contraction of the rat aorta.⁴⁰ Deendothelialization significantly reduced vasodilation of the aorta by 50%. Neither the adenylyl cyclase inhibitor SQ22536 nor the NOS inhibitor L-NMMA reduced urocortin-induced vasodilation.⁴⁰ Urocortin produced both endothelium-dependent and -independent relaxation of rings of human internal mammary arteries.⁴¹ The endothelium-dependent component involves NOS, guanylyl cyclase and BK_Ca channel.⁴¹ Urocortin (3 nM) induced endothelium independent relaxation of isolated rat coronary arteries that were precontracted with phenylephrine or the potent sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin,⁴² while the maximum effect was achieved with a 10 nM concentration. The NOS inhibitor L-NNA, the cyclooxygenase inhibitor indomethacin and the L-type Ca²⁺ channel blocker nifedipine did not abolish this effect of urocortin. Urocortin (10 nM) abolished a thapsigargin-induced increase in intracellular Ca²⁺ in coronary smooth muscle cells (SMC). This effect was eliminated with the CRHR2 antagonist astressin.⁴² Additionally, urocortin inhibited phospholipase A2 expression and activity in SMC. The selective PKA inhibitor KT5720 abolished the urocortin-induced decrease in the Ca²⁺ level in SMC. It was proposed that cAMP, PKA activity and inhibition of Ca²⁺ mobilization from sarcoplasmic reticulum are involved in endothelium independent relaxation of coronary arteries by urocortin.⁴²

Figure 3.

The effects of corticotropin-releasing hormone (CRH) and urocortins (Ucn) on the cardiovascular system.

Intravenous administration of urocortin (0.1-3 nmol/kg) dose-dependently decreased mean arterial pressure in thiobutabarbital-anesthetized rats.⁴³ Neither pretreatment with L-NAME, tetraethylammonium, ATP-sensitive K⁺-channel (K_ATP channel) blocker glibenclamide nor the cyclooxygenase inhibitor indomethacin, affected the hypotensive effect of urocortin. It was concluded that the hypotensive effect of urocortin in anesthetized rats is not mediated via NO, prostanoids and K⁺ channels.⁴³ However, urocortin caused an increase in mean blood pressure (BP) in healthy sheep by increasing cardiac output.⁴⁴ In sheep with heart failure, urocortin also caused an increase in cardiac output, but mean BP decreased, apparently due to the pronounced vasodilator effect.⁴⁴ Urocortin-2 (3.6 to 36 pmol/min) and urocortin-3 (1.2 to 12 nmol/min) infusions did not affect BP in healthy volunteers.⁴⁵ Urocortin caused a transient increase in heart rate.⁴⁵ Urocortin-induced cardiovascular effects or changes in BP by may be dependent on the investigated species or whether the animal was anesthetized or not. The serum urocortin-2 level was increased in patients with mild and moderate congestive heart failure.⁹ Urocortin-2 reduced monocrotaline-induced pulmonary arterial hypertension in rats, decreased morbidity, improved exercise capacity and prevented right ventricular remodeling.⁴⁶

The above data indicate that urocortin induces endothelium-dependent and -independent relaxation of coronary arteries, rat aorta, and human mammary arteries, and a potent, endothelium-independent vasodilation of rat tail arteries and rat pulmonary artery. Urocortin-induced vasodilation can be mediated via NOS, guanylyl cyclase/cGMP, adenylyl cyclase/cAMP, inward-rectifier K⁺ channels, BK_Ca channels, and inhibition of Ca²⁺ mobilization from sarcoplasmic reticulum (Table 1).

It may be hypothesized that NOS, cGMP, cAMP, guanylyl cyclase, BK_Ca channels, and inhibition of Ca²⁺ mobilization from sarcoplasmic reticulum may be involved in the cardioprotective effect of urocortins.

Table 1.

The Vasoprotective Effect of Urocortin, and Vasodilation Induced by CRH and Urocortins.

Compound	Effect	Receptor	Signaling	Authors
Urocortin	I/R Endothelial Dysfunction ↓	Unknown	Unknown	Takatani-Nakase and Takahashi⁴⁷
Urocortin	I/R Endothelial Dysfunction ↓	Unknown	PKC dependent	Williams and Gottlieb⁴⁸
Urocortin-2a Urocortin-3	Vasodilation	Unknown	Unknown	Stirrat et al³³
Urocortin	Vasodilation	CRHR2	AC, BK_Ca channel, K_Ca ² channel dependent	Stirrat et al³³
CRH, Urocortin	Vasodilation	Unknown	PKA dependent	Wiley and Davenport³⁴
Urocortin	Vasodilation	Unknown	NOS dependent GC dependent K⁺ channel dependent	Schilling et al³⁵
Urocortin	Vasodilation	Unknown	BK_Ca channel Dependent PKA-dependent	Lubomirov et al³⁶
Urocortin	Vasodilation	CRHR2	PKA-dependent	Huang et al³⁸
Urocortin	Vasodilation	Unknown	NOS, GC-dependent BK_Ca channel dependent	Chan et al³⁹
Urocortin	Vasodilation	CRHR2	PKA dependent	Miki et al⁴⁰
Urocortin	BP↓	Unknown	Unknown	Chen et al⁴¹
Urocortin	BP↑ healthy sheep	Unknown	Unknown	Smani et al⁴²
Urocortin	BP↓ sheep with heart failure	Unknown	Unknown	Smani et al⁴²
Urocortin-2 Urocortin-3	Had no effect on BP			Abdelrahman et al⁴³

The Role of Urocortins in the Regulation of Cardiomyocyte Contractility

In 1998, it was demonstrated urocortin is expressed in cardiomyocytes.⁴⁹ Urocortin and CRHR2 were found in the left ventricle of the human heart^19,34 and in the rat heart.⁵⁰ Urocortin-2 stimulates contractility of isolated rabbit cardiomyocytes due to activation of CRFR2 and stimulation of PKA.⁵¹ The same authors later confirmed involvement of CRHR2 and PKA in the positive inotropic effect of urocortin-2.⁵² In addition, they found that the inotropic effect of urocortin is associated with the activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Other investigators confirmed this in isolated cardiomyocytes and showed that AMP-activated protein kinase (AMPK) is involved in this effect.⁵³ In a study performed on the isolated rat heart it was demonstrated that urocortion-1 (10 nmol/L) increased left ventricular development pressure (LV DP) and maximum derivative of left ventricular pressure (the contraction rate).⁵⁴

The Cardioprotective Effect of CRF and Urocortins

In neonatal isolated rat cardiomyocytes, administration of urocortin possessed the higher cytoprotective potential against apoptotic death caused by anoxia than CRH.⁵⁵ The cytoprotective and antiapoptotic effect of urocortin is confirmed by studies that were performed on isolated cardiomyocytes under conditions of hypoxia/reoxygenation (H/R).⁵⁶ When peptide (10 nM) was administered before ischemia, urocortin reduced the infarct size/area at risk (IS/AAR) ratio in isolated perfused rat hearts by about 50%. Its administration prior to reperfusion reduced the IS/AAR ratio however, only by about 20%.⁵⁷ The ability of 10 nM urocortin to increase resistance of the isolated rat heart to reperfusion injury was confirmed in other investigations.^58,59 It was demonstrated that extracellular signal-regulated kinase (ERK1/2) is involved in the cardioprotective effect of urocortin during reperfusion.⁵⁹ Urocortin reduced release of lactate dehydrogenase (LDH) and improved cardiac contractility during reperfusion. Moreover, blockade of mitochondrial permeability transition pore (MPT-pore) opening, which triggers apoptosis and cell necrosis, was clearly demonstrated.⁶⁰ Furthermore, pretreatment with urocortin (30 µg/kg) before ischemia decreased the IS/AAR ratio in rats by about 30% and suppressed release of LDH and creatine kinase and reduced the number of apoptotic cardiomyocytes.⁵⁰ The authors were unable to obtain data confirming PKCε and PKCα involvement in the cardioprotective effect of urocortin. In a study performed on isolated rat cardiomyocytes, it was shown that urocortin (10 nmol) increases cell tolerance to H/R by activating PKCε.⁶¹

Intravenous injection of urocortin before coronary occlusion prevented the occurrence and the incidence of reperfusion ventricular tachycardia and fibrillation in rats.⁶² The maximum antiarrhythmic effect was achieved at a dose of 20 μg/kg of urocortin. Interestingly, the infarct-limiting effect appeared already at a dose of 5 μg/kg but reached the maximal effect with a dose of 20 μg/kg. The cardioprotective effect of urocortin was associated with an increase in NO production and a decrease in reactive oxygen species (ROS) formation.⁶² The ability of urocortin to increase antioxidant defense of the heart during in vitro reperfusion is related to PKC activity.⁵⁸ Moreover, urocortin (10 nM) suppressed angiotensin II-induced ROS generation in human umbilical vein endothelial cells (HUVECs),⁶³ which also suggests a downstream connection to PKC.⁶⁴ Later, the specific role of PKCε in cardioprotection elicited by urocortin (10 nM) was confirmed using a PKCε translocation inhibitor peptide in ex vivo perfused hearts and in isolated cardiomyocytes.⁶¹

In addition to PKC, other kinases may be involved in the cardioprotective effect of urocortin. It was reported that a urocortin-induced increase in resistance of atrial murine HL-1 myocytes to H/R, is associated with the activation of tyrosine kinase Src and ERK1/2.⁶⁵ The cytoprotective effect of urocortin was associated with activation of CRHR1, while CRHR2 was not involved in this effect.⁶⁵ However, selective CRHR1 and CRHR2 antagonists were not used in this study, thus presented statement can be considered to be a hypothesis. Experiments performed on isolated rat cardiomyocytes exposed to anoxia, revealed that urocortin inhibited LDH release from cardiomyocytes during anoxia, while the selective CRHR2 antagonist astressin eliminated this cytoprotective effect.⁴⁷ This indicates a role for CRHR2 in the cardioprotective effect of urocortin. Furthermore, pretreatment with the phospholipase-A2 inhibitor bromoenol lactone also exhibited the cytoprotective effect. Anoxia induced the activation of phospholipase-A2 in cardiomyocytes. Both urocortin and bromoenol prevented anoxia-induced activation of phospholipase-A2.⁴⁷ In experiments on isolated rat hearts, bromoenol prevents ischemic injury of the heart, but does not affect reperfusion injury.⁴⁸ Therefore, it can be assumed that the cytoprotective effect of urocortin is mediated via phospholipase-A2 inhibition.

Urocortin-2 increases the amount of phosphorylated (activated) AMPK in isolated rat papillary muscle.⁶⁶ Since the activation of AMPK provides an increase in cardiac tolerance to I/R,⁶⁷ it is likely that this enzyme is involved in the cardioprotective effect of urocortin. In isolated perfused mouse hearts the CRHR2 antagonist anti-sauvagine-30 increased infarct size and exacerbated reperfusion contractile dysfunction.⁶⁶ This fact may suggest that endogenous urocortin provides cardiac tolerance to I/R. However, comparative experiments with CRHR2 antagonists were not performed, so the possibility cannot be ruled out that the negative effect of anti-sauvagine-30 is not related to CRHR2. The selective CRHR2 agonist urocortin-2 (15 µg/kg i.p.) promoted a decrease in the IS/AAR ratio in mice.⁶⁶ Pretreatment with urocortin-2 (100 ng/ml) improved contractility of the isolated perfused heart during reperfusion.⁶⁶ Urocortin-2 increased AMPK activity. Since no AMPK inhibitor was applied, the involvement of AMPK in the cardioprotective effect of peptide remains unclear. The selective PKCε inhibitor εV1-2 abolished the protective effect of urocortin-2.⁶⁶

In a study performed on atrial immortalized mouse cardiomyocytes HL-1, it was demonstrated that urocortin induces interleukin-6 (IL-6) release from cardiomyocytes in a CRHR2-dependent manner.⁶⁸ Urocortin caused rapid Janus kinas-2 (JAK2) phosphorylation. It induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an IL-6-, ERK1/2- and JAK2-dependent manner. It was reported that JAK2 and STAT3 are involved in the cardioprotective effect of post-conditioning⁶⁷ thereby it may be hypothesized that both JAK2 and STAT3 may be also involved in the protective effect of urocotins.

The isolated perfused rat heart was subjected to global ischemia (40 min) and reperfusion (60 min).⁵⁴ Urocortin-1 (10 nmol/L) applied during reperfusion improved post-ischemic recovery of cardiac contractility. It was found that urocortin-1 increased the phosphorylated (activated) ERK1/2 and Epac-2 levels in the myocardium. It was demonstrated that urocortin-1 enhances miR-125a-3p, miR-324-3p expression in the heart but decreases the miR-139-3p level in the myocardium. Urocortin-2 exhibited similar effect on microRNA expression in the heart. Authors suggest that the cardioprotective effect of urocortins is mediated via the activation of CHRH2, an increase in the p-ERK1/2, Epac-2 levels, changes in microRNA.

Not only urocortin, but also CRH possesses a cardioprotective effect. This was confirmed on the isolated perfused rat hearts: CRH (10 nmol) increased cardiac resistance to I/R when used before ischemia but not during reperfusion.⁶⁹ The addition of CRF to the perfusion solution prior to ischemia reduced the IS/AAR ratio by about 40%. The use of CRF during reperfusion did not affect the IS/AAR ratio. The selective CRHR2 antagonist astressin 2B abolished the CRH-induced infarction-limiting effect, while the MEK1/2 and ERK1/2 inhibitor PD 98059 had no effect.⁶⁹ Additionally, a selective PKA inhibitor H-89 eliminated the infarct-reducing effect of CRH, and the selective PKC inhibitor H-7 also acted.⁶⁹ Therefore, the infarction-sparing effect of CRH seems to be associated with PKA and PKC activation. The isolated zebrafish heart was subjected to hypoxia and reoxygenation (H/R).⁷⁰ It was found that CRH and urocortin-3 increases cardiac tolerance to H/R and prevents H/R-induced apoptosis. The ant-apoptotic effect of CRH in zebrafish was confirmed by other investigators.⁷¹

There are data that urocortin-2 can improve acute hemodynamic instability, reduce myocardial damage in post-cardiac arrest myocardial dysfunction in rats.⁷² It increased phosphorylation of Akt, ERK and STAT-3.

A study was carried out on mice with permanent coronary occlusion.⁷³ Chronic administration (30 days) of urocortin-2 (415 μg/kg subcutaneously per day) prevented the development of cardiac hypertrophy, improved cardiac contractility, decreased the collagen-1 mRNA level in left ventricle.

The above data indicate that urocortins and CRH exhibit the protective effect in I/R of the heart ex vivo, and H/R of cardiomyocytes via CRHR2 stimulation, the activation of PKA, PKCε, PKCα, Src, ERK1/2, and inhibition of phospholipase-A2 (Table 2). The possible role of AMPK and ERK1/2 in the cardioprotective effect of CRH and urocortins requires further study. Thus in summary, the abovementioned data are evidence that stimulation of kinases (PKA, PKCε, PKCα, Src, ERK1/2 of PKA, PKCε, PKCα, Src, ERK1/2) may be involved in the infarct-reducing effect of urocortins and CRH.

Table 2.

The Cardioprotective Effect of CRH and Urocortins.

Compound	Effect	Receptor	Signaling	Authors
Urocortin	Infarct-reducingAnti-apoptotic	Unknown	Unknown	Venkatasubramanian et al⁴⁵
Urocortin	Anti-apoptotic	Unknown	Unknown	Yang et al⁵¹
CRH	Anti-apoptotic	Unknown	Unknown	Yang et al⁵¹
Urocortin	Anti-apoptotic	Unknown	Unknown	Yang et al⁵²
Urocortin	Infarct-reducing	Unknown	Unknown	Chen et al⁵³
Urocortin	Anti-necrotic	Unknown	Unknown	Diaz et al⁵⁴
Urocortin	Infarct-reducing	Unknown	ERK1/2↑ dependent	Schulman et al⁵⁹
Urocortin	Anti-necrotic	Unknown	MPT-pore Blocking	Brar et al⁵⁵
Urocortin	Tolerance to H/R	Unknown	PKCε↑	Cserepes et al⁵⁶
Urocortin	Antiarrhythmic	Unknown	Unknown	Brar et al⁵⁷
Urocortin	Infarct-reducing	Unknown	Associated NO↑Associated ROS↓	Brar et al⁵⁷
Urocortin	Tolerance to H/R	CRHR1	Associated Src↑,ERK1/2↑	Halestrap et al⁶⁰
Urocortin	Anti-necrotic	CRHR2	Associated phospholipase-A2↓	Lawrence et al⁶¹
Urocortin-2	Infarct-reducing	CRHR2	PKCε↑ dependent Associated AMPK↑	Honjo et al⁶³
Urocortin-1	Cardiac contractility	Unknown	Associated ERK1/2↑ Epac-2↑miR-125a-3p↑ miR-324-3p↑	Diaz et al⁵⁴
CRH	Infarct-reducing	CRHR2	PKA, PKC dependent	Yuan et al⁶⁵
CRH	Anti-apoptotic	Unknown	Unknown	Williams et al⁷⁰
Urocortin-3Urocortin-2	cardiac contractility	Unknown	Unknown	Ellmers et al⁷³

The Vasoprotective Effect of Urocortin

In isolated perfused rat hearts exposed to ischemia (15 min) and reperfusion (15 min), it was shown that urocortin protects not only cardiomyocytes from I/R injury, but also the endothelium of coronary arteries.^74,75 Relaxation of precontracted coronary arteries in response to acetylcholine was assessed using the thromboxane A2 (TP) receptor agonist U46619. After I/R relaxation of coronary arteries in response to acetylcholine was reduced. Infusion of urocortin (10 pmol) before ischemia and during reperfusion enhanced acetylcholine-induced vasodilation. This urocortin-induced improvement in vasorelaxation in response to acetylcholine was neither modified by the Ca²⁺-dependent K⁺ channel blocker tetraethylammonium, the K_ATP channel blocker glibenclamide, the NO-synthesis inhibitor L-NAME, nor by the cyclooxygenase inhibitor meclofenamate. The PKC inhibitor chelerythrine, abolished the vasoprotective effect of urocortin.⁷⁵ These results indicate that urocortin may protect coronary endothelial function during I/R by activating PKC. The ability of this peptide to enhance the antioxidant protection of endotheliocytes may play a certain role in the vasoprotective effect of urocortin. It is believed that the vasoprotective effect of urocortins is mediated via inhibition of ROS production by endothelial cells.⁹

The abovementioned data demonstrated urocortins can protect coronary arteries against ischemia/reperfusion injury by stimulation of PKC and inhibition of excessive ROS production.

Conclusion

We conclude that CRH and urocortins may increase cardiac resistance to I/R by activating CRHR2, Src, PKA, PKCε, ERK1/2, JAK2 and SAT3 pathways, and by inhibiting phospholipase A2 and MPT-pore. Furthermore, urocortins possess a vasoprotective effect in I/R of the isolated heart by activating PKC. It is known that AMPK, ROS, NO-synthases, JAK2, SAT3, cGMP, PKG, BK_Ca and K_ATP channels play an important role in ensuring cardiac tolerance to I/R.⁶⁷ However, their role in the cardioprotective effect elicited by CRH and urocortins remains unclear. It was established that the cardioprotective effect of urocortins is mediated via the activation of PKA, ERK1/2 and PKCε. It is possible that the cardioprotective effect of urocortins is mediated via changes of microRNA expression. Chronic administration of urocortin-2 prevents the development of postinfarction remodeling of the heart. It is unclear whether urocortins and CRHs can prevent cardiac reperfusion injury in vivo. Similarly, the molecular mechanism involved in the antiarrhythmic effect of urocortins is not known yet. When discussing the possibility of the clinical use of urocortins for treatment of acute myocardial infarction (AMI), attention should be paid to the fact that all urocortins cause tachycardia, which is undesirable in myocardial infarction. In addition, urocortins improve cardiac contractility during in vivo reperfusion. Since cardiogenic shock causing heart failure is the main cause of death in AMI patients, urocortins may find application in treatment of AMI. It is clear that more in vivo studies are needed to clarify this. The data presented in this review indicate that urocortins prevent the occurrence of reperfusion dysfunction of coronary arteries, a positive effect that may be useful in treatment of AMI. Urocortin-1 has good prospects for clinical use, since its effects on hemodynamics persist for a long time.

Footnotes

Acknowledgments

The authors are grateful to the reviewers for advises which improved quality of our article.

Author Contributions

Sergey V. Popov, Ekaterina S. Prokudina, Natalia V. Naryzhnaya, Huijie Ma, Jitka M. Zurmanova and Leonid N. Maslov analyzed published data. Leonid N. Maslov, Alexander V. Mukhomedzyanov, Natalia V. Naryzhnaya searched for data on CRF and urocortins. Leonid N. Maslov corresponded with reviewers. Leonid N. Maslov prepared a preliminary version of manuscript. Alexander V. Mukhomedzyanov prepared figures and a final version of manuscript.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grant from the Russian Foundation of Basic Research 21-515-53003. The section on the localization of CRH and urocortins was prepared with support of the state assignments AAAA-A15-115120910024-0.

ORCID iD

Leonid N. Maslov

References

Guillemin

Rosenberg

. Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures. Endocrinology. 1955;57(5):599-607.

Saffran

Schally

Benefey

. Stimulation of the release of corticotropin from the adenohypophysis by a neurohypophysial factor. Endocrinology. 1955;57(4):439-444.

Spiess

Rivier

Vale

. Primary structure of corticotropin-releasing factor from ovine hypothalamus. Proc Natl Acad Sci USA. 1981;78(10):6517-6521.

Vale

Spiess

Rivier

. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981;213(4514):1394-1397.

Vaughan

Donaldson

Bittencourt

, et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature. 1995;378(6554):287-292.

Reyes

Lewis

Perrin

, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. J Am Coll Cardiol. 2001;98(5):2843-2848.

Hsu

Hsueh

. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med. 2001;7(5):605-611.

Vuppaladhadiam

Ehsan

Akkati

Bhargava

. Corticotropin-releasing factor family: a stress hormone-receptor system’s emerging role in mediating sex-specific signaling. Cells. 2020;9(4):839.

Chatzaki

Kefala

Drosos

Lalidou

Baritaki

. Do urocortins have a role in treating cardiovascular disease? Drug Discov Today. 2019;24(1):279-284.

10.

Kageyama

Bradbury

Zhao

Blount

Vale

. Urocortin messenger ribonucleic acid: tissue distribution in the rat and regulation in thymus by lipopolysaccharide and glucocorticoids. Endocrinology. 1999;140(12):5651-5658.

11.

Tillinger

Nostramo

Kvetnansky

Serova

Sabban

. Stress-induced changes in gene expression of urocortin 2 and other CRH peptides in rat adrenal medulla: involvement of glucocorticoids. J Neurochem. 2013;125(2):185-192.

12.

Patel

Rademaker

Kirkpatrick

, et al. Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep. Br J Pharmacol. 2012;166(6):1916-1925.

13.

Davis

Pemberton

Yandle

, et al. Effect of urocortin 1 infusion in humans with stable congestive cardiac failure. Clin Sci. 2005;109(4):381-388.

14.

Liew

Pang

Hsu

, et al. Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats. J Neuroinflammation. 2012;9:13.

15.

Okada

Suzuki

Travis

Zhang

. The stroke-induced blood-brain barrier disruption: current progress of inspection technique, mechanism, and therapeutic target. Curr Neuropharmacol. 2020;18(12):1.

16.

Kastin

Bjorbaek

Pan

. Urocortin trafficking in cerebral microvessel endothelial cells. J Mol Neurosci. 2007;31(2):171-181.

17.

Squillacioti

Pelagalli

Liguori

Mirabella

. Urocortins in the mammalian endocrine system. Acta Vet Scand. 2019;61(1):46.

18.

Takefuji

Murohara

. Corticotropin-releasing hormone family and their receptors in the cardiovascular system. Circ J. 2019;83(2):261-266.

19.

Kimura

Takahashi

Totsune

, et al. Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol Metab. 2002;87(1):340-346.

20.

Hoare

SRJ

Sullivan

Fan

Khongsaly

Grigoriadis

. Peptide ligand binding properties of the corticotropin-releasing factor (CRF) type 2 receptor: pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivity. Peptides. 2005;26(3):457-470.

21.

Grammatopoulos

. Insights into mechanisms of corticotropin releasing hormone receptor signal transduction. Br J Pharmacol. 2012;166(1):85-97.

22.

Walther

Pluteanu

Renz

, et al. Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt-and PKA-mediated phosphorylation of eNOS at serine 1177. Am J Physiol Heart. 2014;307(5):H689-H700.

23.

Asaba

Makino

Hashimoto

. Effect of urocortin on ACTH secretion from rat anterior pituitary in vitro and in vivo: comparison with corticotropin-releasing hormone. Brain Res. 1998;806(1):95-103.

24.

Tanaka

Telegdy

. Antidepressant-like effects of the CRF family peptides, urocortin 1, urocortin 2 and urocortin 3 in a modified forced swimming test in mice. Brain Res Bull. 2008; 75(5):509-512.

25.

Wagner

. Urocortins and their unfolding role in mammalian social behavior. Cell Tissue Res. 2019;375(1):133-142.

26.

Nemoto

Iwasaki-Sekino

Yamauchi

Shibasaki

. Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats. Am J Physiol Endocrinol Metab. 2010;299(4):E567-E575.

27.

Nakade

Pappas

Takahashi

. Peripheral plasma corticotropin-releasing factor concentration does not correlate with augmented colonic motility in response to restraint stress in rats. Clin Exp Pharmacol Physiol. 2008;35(8):934-937.

28.

. Effect of hypoxia on activity of hypothalamo-pituitary-adrenal-cortex axis in rat. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2001;17(4):317-319.

29.

Tibenska

Benesova

Vebr

, et al. Gradual cold acclimation induces cardioprotection without affecting β-adrenergic receptor-mediated adenylyl cyclase signaling. J Appl Physiol (1985). 2020;128(4):1023-1032.

30.

Tsibulnikov

Maslov

Naryzhnaya

, et al. Impact of cold adaptation on cardiac tolerance to ischemia/reperfusion and glucocorticoid, thyroid hormone levels. Gen Physiol Biophys. 2019;38(3):245-251.

31.

Maslov

Naryzhnaya

Tsibulnikov

, et al. Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia. Life Sci. 2013;93(9-11):373-379.

32.

Wakahashi

Nakabayashi

Maruo

Yata

Ohara

Maruo

. Effects of corticotropin-releasing hormone and stresscopin on vascular endothelial growth factor mRNA expression in cultured early human extravillous trophoblasts. Endocrine. 2008;33(2):144-151.

33.

Stirrat

Venkatasubramanian

Pawade

, et al. Cardiovascular effects of urocortin 2 and urocortin 3 in patients with chronic heart failure. Br J Clin Pharmacol. 2016;82(4):974-982.

34.

Wiley

Davenport

. CRF2 receptors are highly expressed in the human cardiovascular system and their cognate ligands urocortins 2 and 3 are potent vasodilators. Br J Pharmacol. 2004;143(4):508-514.

35.

Schilling

Kanzler

Schmiedek

Ehrenreich

. Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery. Br J Pharmacol. 1998;125(6):1164-1171.

36.

Lubomirov

Gagov

Petkova-Kirova

Duridanova

Kalentchuk

Schubert

. Urocortin relaxes rat tail arteries by a PKA-mediated reduction of the sensitivity of the contractile apparatus for calcium. Br J Pharmacol. 2001;134(7):1564-1570.

37.

Huang

Chan

Lau

, et al. Urocortin-induced endothelium-dependent relaxation of rat coronary artery: role of nitric oxide and K+ channels. Br J Pharmacol. 2002;135(6):1467-1476.

38.

Huang

Chan

Lau

, et al. Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent relaxation by urocortin in the rat coronary artery. Cardiovasc Res. 2003;57(3):824-833.

39.

Chan

Yao

Lau

, et al. The relaxant effect of urocortin in rat pulmonary arteries. Regul Pept. 2004;121(1-3):11-18.

40.

Miki

Seya

Motomura

Furukawa

. Role of corticotropin-releasing factor receptor type 2 beta in urocortin-induced vasodilation of rat aortas. J Pharmacol Sci. 2004;96(2):170-176.

41.

Chen

Huang

Yang

Wei

. Urocortin-induced relaxation in the human internal mammary artery. Cardiovasc Res. 2005;65(4):913-920.

42.

Smani

Domínguez-Rodríguez

Hmadcha

Calderón-Sánchez

Horrillo-Ledesma

Ordóñez

. Role of Ca2+-independent phospholipase A2 and store-operated pathway in urocortin-induced vasodilatation of rat coronary artery. Circ Res. 2007;101(11):1194-1203.

43.

Abdelrahman

Syyong

Tjahjadi

Pang

. Analysis of the mechanism of the vasodepressor effect of urocortin in anesthetized rats. Pharmacology. 2005;7(4):175-179.

44.

Rademaker

Charles

Espiner

, et al. Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep. J Am Coll Cardiol. 2002;40(8):1495-1505.

45.

Venkatasubramanian

Griffiths

McLean

, et al. Vascular effects of urocortins 2 and 3 in healthy volunteers. J Am Heart Assoc. 2013;2(1):e004267.

46.

Adao

Mendes-Ferreira

Santos-Ribeiro

, et al. Urocortin-2 improves right ventricular function and attenuates pulmonary arterial hypertension. Cardiovasc Res. 2018;114(8):1165-1177.

47.

Takatani-Nakase

Takahashi

. Cardioprotective activity of urocortin by preventing caspase-independent, non-apoptotic death in cultured neonatal rat cardiomyocytes exposed to ischemia. Biochem Biophys Res Commun. 2010;402(2):216-221.

48.

Williams

Gottlieb

. Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective. Biochem J. 2002;362(Pt 1):23-32.

49.

Okosi

Brar

Chan

, et al. Expression and protective effects of urocortin in cardiac myocytes. Neuropeptides. 1998;32(2):167-171.

50.

Cong

Zhu

Cao

Xiao

Wang

. Estrogens protect myocardium against ischemia/reperfusion insult by up-regulation of CRH receptor type 2 in female rats. Int J Cardiol. 2013;168(5):4755-4760.

51.

Yang

Kockskämper

Heinzel

, et al. Urocortin II enhances contractility in rabbit ventricular myocytes via CRF2 receptor mediated stimulation of protein kinase A. Cardiovasc Res. 2006;69(2):402-411.

52.

Yang

Kockskämper

Khan

, et al. cAMP-and Ca2+/calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes. Br J Pharmacol. 2011;162(2):544-556.

53.

Chen

Wang

, et al. The modulation of cardiac contractile function by the pharmacological and toxicological effects of urocortin 2. Toxicol Sci. 2015;148(2):581-593.

54.

Diaz

Calderón-Sánchez

Toro

, et al. miR-125a, miR-139 and miR-324 contribute to urocortin protection against myocardial ischemia-reperfusion injury. Sci Rep. 2017;7(1):8898.

55.

Brar

Stephanou

Okosi

, et al. CRH-like peptides protect cardiac myocytes from lethal ischaemic injury. Mol Cell Endocrinol. 1999;158(1-2):55-63.

56.

Cserepes

Jancsó

Gasz

, et al. Cardioprotective action of urocortin in early pre- and postconditioning. Ann N Y Acad Sci. 2007;1095:228-239.

57.

Brar

Jonassen

Stephanou

, et al. Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem. 2000;275(12):8508-8514.

58.

Townsend

Davidson

Clarke

, et al. Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress. Am J Physiol Heart Circ Physiol. 2007;293(2):H928-H938.

59.

Schulman

Latchman

Yellon

. Urocortin protects the heart from reperfusion injury via upregulation of p42/p44 MAPK signaling pathway. Am J Physiol Heart Circ Physiol. 2002;283(4):H1481-H1488.

60.

Halestrap

Clarke

Javadov

. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res. 2004;61(3):372-385.

61.

Lawrence

Kabir

Bellahcene

, et al. Cardioprotection mediated by urocortin is dependent on PKCε activation. FASEB J. 2005;19(7):831-833.

62.

Liu

Yang

Liu

. In vivo protective effects of urocortin on ischemia-reperfusion injury in rat heart via free radical mechanisms. Can J Physiol Pharmacol. 2005;83(6):459-465.

63.

Honjo

Inoue

Shiraki

, et al. Endothelial urocortin has potent antioxidative properties and is upregulated by inflammatory cytokines and pitavastatin. J Vasc Res. 2006;43(2):131-138.

64.

Malhotra

Kang

Opawumi

Belizaire

Meggs

. Molecular biology of protein kinase C signaling in cardiac myocytes. Mol Cell Biochem. 2001;225(1):97-107.

65.

Yuan

McCauley

Chen-Scarabelli

, et al. Activation of Src protein tyrosine kinase plays an essential role in urocortin-mediated cardioprotection. Mol Cell Endocrinol. 2010;325(1-2):1-7.

66.

Cheng

, et al. Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart. Proc Natl Acad Sci USA. 2013;110(40):16133-16138.

67.

Heusch

. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res. 2015;116(4):674-699.

68.

Corsetti

Yuan

Romano

, et al. Urocortin induces phosphorylation of distinct residues of signal transducer and activator of transcription 3 (STAT3) via different signaling pathways. Med Sci Monit Basic Res. 2019;25:139-152.

69.

Jonassen

Wergeland

Helgeland

Mjøs

Brar

. Activation of corticotropin releasing factor receptor type 2 in the heart by corticotropin releasing factor offers cytoprotection against ischemic injury via PKA and PKC dependent signaling. Regul Pept. 2012;174(1-3):90-97.

70.

Williams

Bergstrome

Scott

Bernier

. CRF and urocortin 3 protect the heart from hypoxia/reoxygenation-induced apoptosis in zebrafish. Am J Physiol Regul Integr Comp Physiol. 2017;313(2):R91-R100.

71.

Alderman

Leishman

Fuzzen

MLM

Bernier

. Corticotropin-releasing factor regulates caspase-3 and may protect developing zebrafish from stress-induced apoptosis. Am J Physiol Regul Integr Comp Physiol. 2017;313(2):R91-R100.

72.

Huang

Wang

Tsai

, et al. Urocortin treatment improves acute hemodynamic instability and reduces myocardial damage in post-cardiac arrest myocardial dysfunction. PLoS One. 2016;11(11):e0166324.

73.

Ellmers

Scott

Cameron

Richards

Rademaker

. Chronic urocortin 2 administration improves cardiac function and ameliorates cardiac remodeling after experimental myocardial infarction. J Cardiovasc Pharmacol. 2015;65(3):269-275.

74.

Garcia-Villalon

Sanz

Monge

Fernández

Climent

Diéguez

. Urocortin protects coronary endothelial function during ischemia-reperfusion: a brief communication. Exp Biol Med (Maywood). 2004;229(1):118-120.

75.

Garcia-Villalón

Amezquita

Monge

, et al. Mechanisms of the protective effects of urocortin on coronary endothelial function during ischemia-reperfusion in rat isolated hearts. Br J Pharmacol. 2005;145(4):490-494.

Cardioprotective and Vasoprotective Effects of Corticotropin-Releasing Hormone and Urocortins: Receptors and Signaling

Abstract

Keywords

Introduction

Localization of CRH and Urocortins in Organs and Tissues

CRH Receptors

CRH and Urocortins in Stress

CRH and Urocortin-Induced Vasodilation

The Role of Urocortins in the Regulation of Cardiomyocyte Contractility

The Cardioprotective Effect of CRF and Urocortins

The Vasoprotective Effect of Urocortin

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References