Loss of the p47phox subunit or Ang 1-7 supplementation in ACE2 knockout mice normalized increased NADPH oxidase activity, superoxide production, and systolic dysfunction following pressure overload.
Does loss of p47phox or Ang 1-7 supplementation prevent enhanced susceptibility to biomechanical stress and heart failure in ACE2 null mice?
In ACE2-deficient mice, biomechanical stress activates the myocardial NADPH oxidase system via the p47phox subunit, leading to adverse remodeling that can be prevented by p47phox deletion or Ang 1-7 supplementation.
AIMS: Angiotensin-converting enzyme 2 (ACE2) is an important negative regulator of the renin-angiotensin system. Loss of ACE2 enhances the susceptibility to heart disease but the mechanism remains elusive. We hypothesized that ACE2 deficiency activates the NADPH oxidase system in pressure overload-induced heart failure. METHODS AND RESULTS: Using the aortic constriction model, we subjected wild-type (Ace2(+/y)), ACE2 knockout (ACE2KO, Ace2(-/y)), p47(phox) knockout (p47(phox)KO, p47(phox-)(/-)), and ACE2/p47(phox) double KO mice to pressure overload. We examined changes in peptide levels, NADPH oxidase activity, gene expression, matrix metalloproteinases (MMP) activity, pathological signalling, and heart function. Loss of ACE2 resulted in enhanced susceptibility to biomechanical stress leading to eccentric remodelling, increased pathological hypertrophy, and worsening of systolic performance. Myocardial angiotensin II (Ang II) levels were increased, whereas Ang 1-7 levels were lowered. Activation of Ang II-stimulated signalling pathways in the ACE2-deficient myocardium was associated with increased expression and phosphorylation of p47(phox), NADPH oxidase activity, and superoxide generation, leading to enhanced MMP-mediated degradation of the extracellular matrix. Additional loss of p47(phox) in the ACE2KO mice normalized the increased NADPH oxidase activity, superoxide production, and systolic dysfunction following pressure overload. Ang 1-7 supplementation suppressed the increased NADPH oxidase and rescued the early dilated cardiomyopathy in pressure-overloaded ACE2KO mice. CONCLUSION: In the absence of ACE2, biomechanical stress triggers activation of the myocardial NAPDH oxidase system with a critical role of the p47(phox) subunit. Increased production of superoxide, activation of MMP, and pathological signalling leads to severe adverse myocardial remodelling and dysfunction in ACE2KO mice.
Bodiga et al. (Tue,) conducted a other in Pressure overload-induced heart failure. Loss of p47phox (double knockout) or Ang 1-7 supplementation vs. ACE2 knockout mice and wild-type mice was evaluated on Changes in peptide levels, NADPH oxidase activity, gene expression, MMP activity, pathological signalling, and heart function. Loss of the p47phox subunit or Ang 1-7 supplementation in ACE2 knockout mice normalized increased NADPH oxidase activity, superoxide production, and systolic dysfunction following pressure overload.
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