Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit
| Autor: | George C. Liu, Zamaneh Kassiri, Sreedhar Bodiga, Danny Guo, Wang Wang, Jennifer Lo, Josef M. Penninger, Steven M. Holland, James W. Scholey, Ratnadeep Basu, Gavin Y. Oudit, Jiu Chang Zhong |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Time Factors Physiology Blood Pressure medicine.disease_cause Ventricular Function Left Mice chemistry.chemical_compound Superoxides Phosphorylation Mice Knockout Oxidase test NADPH oxidase Ventricular Remodeling Superoxide Angiotensin II Extracellular Matrix Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 Cardiology and Cardiovascular Medicine hormones hormone substitutes and hormone antagonists Cardiomyopathy Dilated medicine.medical_specialty Peptidyl-Dipeptidase A Biology Physiology (medical) Internal medicine medicine Animals Ventricular remodeling Heart Failure Pressure overload Analysis of Variance Myocardium NADPH Oxidases Original Articles medicine.disease Matrix Metalloproteinases Peptide Fragments Enzyme Activation Mice Inbred C57BL Disease Models Animal Oxidative Stress Endocrinology chemistry biology.protein Stress Mechanical Angiotensin I Oxidative stress |
| Zdroj: | Cardiovascular Research. 91:151-161 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvr036 |
| Popis: | 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 ), p47phox knockout (p47phoxKO, p47phox− /−), and ACE2/p47phox 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 p47phox, NADPH oxidase activity, and superoxide generation, leading to enhanced MMP-mediated degradation of the extracellular matrix. Additional loss of p47phox 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 p47phox subunit. Increased production of superoxide, activation of MMP, and pathological signalling leads to severe adverse myocardial remodelling and dysfunction in ACE2KO mice. |
| Databáze: | OpenAIRE |
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