Angiotensin-converting enzyme 3 (ACE3) protects against pressure overload-induced cardiac hypertrophy

Background--angiotensin-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 results--neonatal 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. conclusions--our comprehensive analyses suggest that ace3 inhibits pressure overload-induced cardiac hypertrophy by blocking the mek-erk1/2 signaling pathway. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.