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

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Enzymology

Background:

• Angiotensin-converting enzyme 3 (ACE3) is a newly identified homolog of ACE.
• The precise pathophysiological role of ACE3 remains largely uncharacterized.
• This study investigates ACE3's function in pathological cardiac hypertrophy.

Purpose of the Study:

• To elucidate the role of ACE3 in the development of cardiac hypertrophy.
• To determine the molecular mechanisms by which ACE3 influences cardiac remodeling.
• To assess the therapeutic potential of targeting ACE3 in heart disease.

Main Methods:

• Utilized neonatal rat cardiomyocytes (NRCMs) with manipulated ACE3 expression (gain and loss of function).
• Employed mouse models with global ACE3 knockout and cardiac-specific ACE3 overexpression.
• Induced cardiac hypertrophy via aortic banding (AB) in mice, followed by comprehensive echocardiographic, pathological, and molecular analyses.

Main Results:

• ACE3 expression protected cultured cardiomyocytes against angiotensin II-induced hypertrophy.
• ACE3-deficient mice showed exacerbated cardiac hypertrophy, fibrosis, and reduced contractile function post-aortic banding.
• Cardiac-specific ACE3 overexpression attenuated the hypertrophic response compared to controls.
• ACE3 inhibited cardiac hypertrophy by suppressing the MEK-ERK1/2 signaling pathway.

Conclusions:

• ACE3 plays a significant inhibitory role in pressure overload-induced cardiac hypertrophy.
• The protective effect of ACE3 is mediated through the blockade of the MEK-ERK1/2 signaling pathway.
• Targeting ACE3 may represent a novel therapeutic strategy for managing cardiac hypertrophy.