RRC ID 36005
Author Yu CJ, Tang LL, Liang C, Chen X, Song SY, Ding XQ, Zhang KY, Song BL, Zhao D, Zhu XY, Li HL, Zhang ZR.
Title Angiotensin-Converting Enzyme 3 (ACE3) Protects Against Pressure Overload-Induced Cardiac Hypertrophy.
Journal J Am Heart Assoc
Abstract 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.
Volume 5(2)
Published 2016-2-18
DOI 10.1161/JAHA.115.002680
PII JAHA.115.002680
PMID 26892527
PMC PMC4802478
MeSH Animals Animals, Newborn Aorta / physiopathology Aorta / surgery Arterial Pressure* Cardiomegaly / enzymology Cardiomegaly / genetics Cardiomegaly / pathology Cardiomegaly / prevention & control* Cells, Cultured Disease Models, Animal Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases / metabolism Fibrosis Ligation MAP Kinase Kinase Kinases / antagonists & inhibitors MAP Kinase Kinase Kinases / metabolism Mice, Inbred C57BL Mice, Knockout Myocytes, Cardiac / drug effects Myocytes, Cardiac / enzymology* Myocytes, Cardiac / pathology Peptidyl-Dipeptidase A / deficiency Peptidyl-Dipeptidase A / genetics Peptidyl-Dipeptidase A / metabolism* Protein Kinase Inhibitors / pharmacology Rats, Sprague-Dawley Signal Transduction Transfection
IF 4.605
Times Cited 4
Mice RBRC04138