Anjana Siva

Involvement of Nox2 NADPH Oxidase in Adverse Cardiac Remodeling After Myocardial Infarction

Oxidative stress plays an important role in the development of cardiac remodeling after myocardial infarction (MI), but the sources of oxidative stress remain unclear. We investigated the role of Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase in the development of cardiac remodeling after MI. Adult Nox2−/− and matched wild-type (WT) mice were subjected to coronary artery ligation and studied 4 weeks later. Infarct size after MI was similar in Nox2−/− and WT mice. Nox2−/− mice exhibited significantly less left ventricular (LV) cavity dilatation and dysfunction after MI than WT mice (eg, echocardiographic LV end-diastolic volume: 75.7±5.8 versus 112.4±12.3 μL; ejection fraction: 41.6±3.7 versus 32.9±3.2%; both P<0.05). Similarly, in vivo LV systolic and diastolic functions were better preserved in Nox2−/− than WT mice (eg, LV dP/dtmax: 7969±385 versus 5746±234 mm Hg/s; LV end-diastolic pressure: 12.2±1.3 versus 18.0±1.8 mm Hg; both P<0.05). Nox2−/− mice exhibited less cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis; reduced increases in expression of connective tissue growth factor and procollagen 1 mRNA; and smaller increases in myocardial matrix metalloproteinase–2 activity than WT mice. These data suggest that the Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase contributes significantly to the processes underlying adverse cardiac remodeling and contractile dysfunction post-MI.

Defective peroxisomal proliferators activated receptor gamma activity due to dominant- negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPARγ) typically develop a complex metabolic syndrome characterized by insulin resistance, diabetes, lipodystrophy, hypertension, and dyslipidaemia which is likely to increase their cardiovascular risk. Despite evidence that the activation of PPARγ may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPARγ causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPARγ function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant‐negative mutation in PPARγ.