Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit

摘要: Aims Angiotensin-converting enzyme 2 (ACE2) is an important negative regulator of the renin-angiotensin system. Loss ACE2 enhances susceptibility to heart disease but mechanism remains elusive. We hypothesized that deficiency activates NADPH oxidase system in pressure overload-induced failure. Methods and results Using aortic constriction model, we subjected wild-type ( Ace2+/y ), knockout (ACE2KO, Ace2−/y p47phox (p47phoxKO, p47phox− /−), ACE2/p47phox double KO mice overload. examined changes peptide levels, activity, gene expression, matrix metalloproteinases (MMP) pathological signalling, function. resulted enhanced biomechanical stress leading eccentric remodelling, increased hypertrophy, worsening systolic performance. Myocardial angiotensin II (Ang II) levels were increased, whereas Ang 1–7 lowered. Activation II-stimulated signalling pathways ACE2-deficient myocardium was associated with expression phosphorylation p47phox, superoxide generation, MMP-mediated degradation extracellular matrix. Additional loss ACE2KO normalized production, dysfunction following supplementation suppressed rescued early dilated cardiomyopathy pressure-overloaded mice. Conclusion In absence ACE2, triggers activation myocardial NAPDH a critical role subunit. Increased production superoxide, MMP, leads severe adverse remodelling mice.