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Abstract

This study investigated renin–angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically and the hearts were excised for molecular and immunohistochemical analyses. Echocardiographic studies revealed that four weeks of RAS-stimulation incited a cardiac remodeling process characterized by increased left ventricular (LV) wall thickness, decreased LV volumes, and shortening of the left ventricle. Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR.

Keywords

Renin–angiotensin system Cyp1a1-Ren2 transgenic rat cardiac remodeling hypertrophy fibrosis heart failure

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References

Schellings

Pinto

Heymans

. Matricellular proteins in the heart: Possible role during stress and remodeling. Cardiovasc Res 2004; 64: 24–31.

Bader

. Role of the local renin-angiotensin system in cardiac damage: A minireview focussing on transgenic animal models. J Mol Cell Cardiol 2002; 34: 1455–1462.

Mullins

Bailey

Mullins

. Hypertension, kidney, and transgenics: A fresh perspective. Physiol Rev 2006; 86: 709–746.

Kantachuvesiri

Fleming

Peters

. Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem 2001; 276: 36727–36733.

Heijnen

BFJ

Peutz-Kootstra

Mullins

. Transient renin-angiotensin system stimulation in an early stage of life causes sustained hypertension in rats. J Hypertens 2011; 29: 2369–2380.

Howard

Mullins

Mitchell

. Transient induction of ANG II-dependent malignant hypertension causes sustained elevation of blood pressure and augmentation of the pressor response to ANG II in CYP1A1-REN2 transgenic rats. Am J Med Sci 2010; 339: 543–548.

Mitchell

Mullins

. Enhanced tubuloglomerular feedback in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 2005; 289: F1210–F1216.

Graciano

Mouton

Patterson

. Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 2007; 292: F1858–F1866.

De Boer

Pokharel

Flesch

. Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27. J Mol Med 2004; 82: 678–687.

10.

Rothermund

Pinto

Vetter

. Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene. J Hypertens. 2001; 19: 1465–1472.

11.

Seccia

Belloni

Kreutz

. Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II. J Am Coll Cardiol 2003; 41: 666–673.

12.

Villarreal

MacKenna

Omens

. Myocardial remodeling in hypertensive Ren-2 transgenic rats. Hypertension 1995; 25: 98–104.

13.

Whaley-Connell

Habibi

Cooper

. Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat. Am J Physiol Endocrinol Metab 2008; 295: E103–E109.

14.

Schroen

Heymans

Sharma

. Thrombospondin-2 is essential for myocardial matrix integrity: Increased expression identifies failure-prone cardiac hypertrophy. Circ Res 2004; 95: 515–522.

15.

Vanourkova

Kramer

Huskova

. AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension. J Hypertens 2006; 24: 2465–2472.

16.

Van Esch

Van Veghel

Garrelds

. Handle region peptide counteracts the beneficial effects of the Renin inhibitor aliskiren in spontaneously hypertensive rats. Hypertension 2011; 57: 852–858.

17.

Van de Schans

Van den Borne

Strzelecka

. Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy. Hypertension 2007; 49: 473–480.

18.

Damoiseaux

Dopp

Calame

Chao

MacPherson

Dijkstra

. Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology. 1994; 83: 140–147.

19.

Montgomery

Kiernan

Whitworth

. Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27. J Hypertens 1998; 16: 635–643.

20.

Peters

Schluter

Riegel

. Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism. Am J Physiol Heart Circ Physiol. 2009; 297: H1845–1852.

21.

Kim

Ohta

Hamaguchi

. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 1995; 25: 1252–1259.

22.

Bader

Zhao

Sander

. Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats. Hypertension 1992; 19: 681–686.

23.

Veniant

Menard

Bruneval

. Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 1996; 98: 1966–1970.

24.

Whitworth

Fleming

Cumming

. Spontaneous development of malignant phase hypertension in transgenic Ren-2 rats. Kidney Int 1994; 46: 1528–1532.

25.

Kantachuvesiri

Haley

Fleming

. Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats. Kidney Int 1999; 56: 414–420.

26.

Notohamiprodjo

Djafarzadeh

Mojaat

. Generation of GPI-linked CCL5 based chemokine receptor antagonists for the suppression of acute vascular damage during allograft transplantation. Protein Eng Des Sel 2006; 19: 27–35.

27.

Klotz

Burkhoff

Garrelds

. The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: Therapeutic consequences? Eur Heart J 2009; 30: 805–812.

28.

Danser

Van Kats

Admiraal

. Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis. Hypertension 1994; 24: 37–48.

29.

Pinto

Pinto-Sietsma

Philipp

. Reduction in left ventricular messenger RNA for transforming growth factor beta(1) attenuates left ventricular fibrosis and improves survival without lowering blood pressure in the hypertensive TGR(mRen2)27 Rat. Hypertension 2000; 36: 747–754.

30.

Baumann

Janssen

Hermans

. Transient AT1 receptor-inhibition in prehypertensive spontaneously hypertensive rats results in maintained cardiac protection until advanced age. J Hypertens 2007; 25: 207–215.

31.

Wang

Khoury

Yue

. Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure. Eur Heart J 2008; 29: 1283–1289.

32.

Reudelhuber

Bernstein

Delafontaine

. Is angiotensin II a direct mediator of left ventricular hypertrophy? Time for another look. Hypertension 2007; 49: 1196–1201.

33.

Kurdi

Booz

. New take on the role of angiotensin II in cardiac hypertrophy and fibrosis. Hypertension 2011; 57: 1034–1038.

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Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

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