Is Angiotensin II a Direct Mediator of Left Ventricular Hypertrophy?

Reudelhuber, Timothy L.; Bernstein, Kenneth E.; Delafontaine, Patrick

doi:10.1161/hypertensionaha.106.075085

Cited by 76 publications

(56 citation statements)

References 58 publications

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“…The IHR model constitutes a unique opportunity to study the molecular pathways of both induction and regression of myocardial remodeling. The role of Ang II as a direct mediator of LV remodeling has been studied extensively, leading to the conclusion that Ang II alone is not sufficient to induce a remodeling response 32 Our current data are in line with these studies and indicate that differences in matricellular remodeling rather than pathological adaptations in myocyte function underlie the disparity in ventricular remodeling of IHR and TGR. A recent review by Kurdi and Booz 33 puts these data in perspective, describing that Ang II needs additional factors, e.g.…”

Section: Several Factors May Have Contributed To the Characteristic Csupporting

confidence: 84%

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

Heijnen

Pelkmans

Danser

et al. 2013

J Renin Angiotensin Aldosterone Syst

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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.

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Section: Several Factors May Have Contributed To the Characteristic Csupporting

confidence: 84%

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

Heijnen

Pelkmans

Danser

et al. 2013

J Renin Angiotensin Aldosterone Syst

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“…Recent evidence has indicated that cardiac Ang II levels are implicated in the induction of fibrosis, but Ang II is not required for left ventricle hypertrophy (30). Using transgenic animal models for RAS components it has been shown that accentuated formation of local Ang II in the heart (20-to 50-fold greater than the levels seen in control groups) was not responsible for the development of the hypertrophy observed.…”

Section: Exercise-induced Cardiac Hypertrophy Via At1 Receptormentioning

confidence: 99%

“…In the same study, using another type of transgenic mouse that overexpressed a degradation-resistant form of Ang II, the hormone levels reached 100-fold the normal levels and began to spill into the circulation. Although an increase in fibrosis was shown, hypertrophy continued only when an excess amount of cardiac Ang II entered the circulation and caused an increase in BP (30,31). More recently, Xiao et al (32) reported that in mice expressing ACE only in the heart the increase in cardiac Ang II was not associated with cardiac hypertrophy, indicating that the increase of cardiac Ang II was not sufficient to induce hypertrophy.…”

Section: Exercise-induced Cardiac Hypertrophy Via At1 Receptormentioning

confidence: 99%

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

Fernandes

Soci

Oliveira

2011

Braz J Med Biol Res

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“…Given this, we tested to determine whether chymase limits ACE inhibitor efficacy in the post-MI heart. The adult mouse heart has chymase activity, but a direct Ang II effect on cardiomyocytes in vivo is not easily demonstrable (30,31). We chose the hamster as a model system because Ang II-forming chymase activity and chymase-to-ACE activity ratio in hamster heart homogenates is similar to that observed in humans (32) and, as in the human heart (33), Ang II produces a positive inotropic effect in the hamster heart (21,34).…”

Section: Chronic Ace Inhibition Causes Chymase Release Into the LV Ismentioning

confidence: 99%

“…The mouse model has a second limitation in that its cardiomyocytes in vivo from adult animals are relatively unresponsive to Ang II (30,31). This led us to choose the hamster for functional studies.…”

Section: Figurementioning

confidence: 99%

Mast cell chymase limits the cardiac efficacy of Ang I–converting enzyme inhibitor therapy in rodents

Wei¹,

Hase²,

Inoue³

et al. 2010

J. Clin. Invest.

133

147

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Ang I-converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang IIforming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor-mediated increase in LV ISF chymase activity that was not observed in mast cell-deficient Kit W /Kit W-v mice. In chronic ACE inhibitor-treated mast cell-sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.

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Is Angiotensin II a Direct Mediator of Left Ventricular Hypertrophy?

Cited by 76 publications

References 58 publications

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

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

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

Mast cell chymase limits the cardiac efficacy of Ang I–converting enzyme inhibitor therapy in rodents

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