Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

Zhong, Jiu-Chang; Basu, Ratnadeep; Guo, Danny; Chow, Fung L.; Byrns, Simon; Schuster, Manfred; Loibner, Hans; Wang, Xiuhua; Penninger, Josef; Kassiri, Zamaneh; Oudit, Gavin Y.

doi:10.1161/circulationaha.110.955369

Cited by 400 publications

(495 citation statements)

References 42 publications

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“…Consistent with this, further in vivo studies using genetically engineered mice also found that ACE3 provides protective effects against chronic pressure overload‐induced cardiac hypertrophy, fibrosis, and dysfunction. Accumulating evidence has pointed out that ACE2 and its primary product Ang 1 to 7 play critical roles in the pathophysiology of cardiovascular disease, especially the protective actions against pathological cardiac hypertrophy 20, 21. We demonstrated that ACE3, as a new component of the ACE family, has the ability to impair Ang II‐ and pressure overload‐induced cardiac hypertrophy in this study.…”

Section: Discussionsupporting

confidence: 58%

“…Our present findings are also consistent with the ability of the increased activation of MEK‐ERK1/2 signaling to exacerbate the pathological cardiac hypertrophy observed in other studies. Previous studies have demonstrated that the antagonistic roles of ACE2 on the worsening cardiac fibrosis and pathological hypertrophy were associated with the inhibition of the ERK1/2 signaling activity, which was markedly increased in ACE2‐deficient mice in response to pressure overload 20. Carabin, a protein expressed mainly in the immune system and the heart, was shown as a negative regulator of cardiac hypertrophy that induced by pressure overload and adrenergic stimulation, partly though inhibition of the MEK‐ERK1/2 signaling 24.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

Tang

Chen

et al. 2016

JAHA

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BackgroundAngiotensin‐converting enzyme 3 (ACE3) is a recently defined homolog of ACE. However, the pathophysiological function of ACE3 is largely unknown. Here, we aim to explore the role of ACE3 in pathological cardiac hypertrophy.Methods and ResultsNeonatal rat cardiomyocytes (NRCMs) with gain and loss of function of ACE3 and mice with global knockout or cardiac‐specific overexpression of ACE3 were used in this study. In cultured cardiomyocytes, ACE3 conferred protection against angiotensin II (Ang II)‐induced hypertrophic growth. Cardiac hypertrophy in mice was induced by aortic banding (AB) and the extent of hypertrophy was analyzed through echocardiographic, pathological, and molecular analyses. Our data demonstrated that ACE3‐deficient mice exhibited more pronounced cardiac hypertrophy and fibrosis and a strong decrease in cardiac contractile function, conversely, cardiac‐specific ACE3‐overexpressing mice displayed an attenuated hypertrophic phenotype, compared with control mice, respectively. Analyses of the underlying molecular mechanism revealed that ACE3‐mediated protection against cardiac hypertrophy by suppressing the activation of mitogen‐activated protein kinase kinase (MEK)‐regulated extracellular signal‐regulated protein kinase (ERK1/2) signaling, which was further evidenced by the observation that inhibition of the MEK‐ERK1/2 signaling by U0126 rescued the exacerbated hypertrophic phenotype in ACE3‐deficient mice.ConclusionsOur comprehensive analyses suggest that ACE3 inhibits pressure overload‐induced cardiac hypertrophy by blocking the MEK‐ERK1/2 signaling pathway.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

Tang

Chen

et al. 2016

JAHA

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“…S1D). Two weeks after injection with rAAV9‐CYP2J2, the mice were exposed to 14 days of continuous infusion of either a saline control or Ang II (1 mg kg −1 day −1 ) to induce chronic hypertension and cardiac hypertrophy (Zhong et al ., 2010). Heart size was evaluated at the end of the 14‐day treatment period.…”

Section: Resultsmentioning

confidence: 99%

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

et al. 2016

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SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

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Section: Article See P 1322mentioning

confidence: 99%

“…6 Intriguingly, treatment of wild type mice with recombinant human ACE2 reverses Ang II-induced pathological hypertrophy and oxidative stress. 6 In addition, recombinant human ACE2 therapy also attenuates the deterioration in cardiac function and development of pathological hypertrophy in wild type mice subjected to pressure overload via aortic banding. 6 Aortic banding of ACE2KO mice exacerbates the progression of LV hypertrophy, LV dilatation, and systolic dysfunction, which is associated with increased NADPH oxidase activity and subsequent oxidative stress, and is amendable to reversal following Ang 1-7 supplementation.…”

Section: Article See P 1322mentioning

confidence: 99%

An ACE Up Your Sleeve

Ussher¹,

Lopaschuk²

2012

Circulation Research

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A lthough the renin angiotensin system (RAS) is a well established regulator of blood pressure and intravascular volume, 1 considerable evidence has emerged demonstrating the importance of the RAS directly on the cardiovascular system (please refer to the Figure for description of the enzymatic pathways involved in RAS regulation). Indeed, angiotensin converting enzyme (ACE) inhibitors, which prevent the conversion of angiotensin I into angiotensin II (Ang II), and Ang II receptor type 1 (AT1R) antagonists, which inhibit the receptor-mediated actions of Ang II, have demonstrated direct favorable effects on the heart. These include a reduction in cardiac fibrosis during hypertensive left ventricular (LV) hypertrophy, protection against LV enlargement following myocardial infarction, and reduced LV remodeling following coronary artery bypass graft surgery. 2 Hence, ACE1 is generally thought of as a villain contributing to the development of cardiovascular disease due to its generation of Ang II. Fortunately, the RAS may also have a potential hero in ACE2, which can counter many of the negative consequences of ACE1-produced Ang II. In this issue of Circulation Research, Patel et al 3 demonstrate an important role for the RAS in the development of diabetic cardiomyopathy. If diabetic Akita mice are deficient for ACE2 (Akita/ ACE2KO), the enzyme responsible for converting Ang II into Ang 1-7, a progressive systolic dysfunction occurred that is associated with oxidative stress, excessive extracellular matrix degradation, vascular dysfunction, and impairment of the Akt-signaling pathway. Ang II activation of the AT1R was implicated in these actions, since a 1-month treatment with the AT1R antagonist, irbesartan, reversed this systolic dysfunction, oxidative stress, vascular dysfunction, and Akt signaling in the Akita/ACE2KO mice. Article, see p 1322These findings add to the growing body of evidence implicating a cardioprotective role for ACE2 in cardiovascular diseases. Initial interest in ACE2 as a potential therapeutic target for cardiovascular diseases was engendered by the observation that ace2 mapped to several putative genetic quantitative trait loci associated with hypertension in 3 rodent models of elevated blood pressure. 4 Moreover, the generation of mice deficient for ACE2 (ACE2KO) was associated with a phenotype exhibiting LV contractile dysfunction. 4 Subsequent studies illustrated that ACE2 may be a potential cardioprotective target in a variety of cardiac pathologies. Indeed, ACE2KO mice are more susceptible to ischemic injury, adverse LV remodeling, and LV contractile dysfunction following permanent occlusion of the left anterior descending coronary artery. 5 These effects are prevented by treatment with irbesartan for 3 days prior to left anterior descending coronary artery occlusion and for the duration of the study. 5 Chronic infusion of Ang II into mice also exacerbates pathological hypertrophy, oxidative stress, myo-

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Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

Cited by 400 publications

References 42 publications

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

An ACE Up Your Sleeve

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