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

Abstract

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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“…Western blot analysis was performed as previously described . Total protein was extracted from the liver tissues and cultured cells with lysis buffer.…”

“…Real-time PCR was performed as previously described. (21,22) Briefly, after total RNA isolation and cDNA synthesis, real-time PCR was conducted with the LightCycler 480 QPCR System (Roche). The relative quantity of the targeted RNA was calculated through normalization to the quantity of the corresponding β-actin mRNA level.…”

“…Western blot analysis was performed as previously described. (21,22) Total protein was extracted from the liver tissues and cultured cells with lysis buffer. Then, the protein samples were separated by gel electrophoresis and transferred to a polyvinylidene fluoride membrane.…”

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“…Pathological cardiac hypertrophy is usually induced by pressure overload and continuous β-adrenergic receptor (β-AR)-activation, such as hypertension, ischemia, myocarditis and so on. Although the initial hypertrophic phase can indeed maintain cardiac output, continued pathological hypertrophy can destroy its beneficial effects and eventually lead to malignant arrhythmias, heart failure and sudden death [1][2][3]. Understanding the key molecular events that mediate pathological hypertrophy is critical to developing new therapeutic strategies to prevent morbidity and mortality associated with myocardial hypertrophy.…”