Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of post-infarct heart failure in type 2 diabetes.

Am J Physiol Heart Circ Physiol. 2009 May 22; Matsushima S, Kinugawa S, Yokota T, Inoue N, Ohta Y, Hamaguchi S, Tsutsui HType 2 diabetes adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) failure. NAD(P)H oxidase-derived superoxide (O2(-)) production is increased in type 2 diabetes. However, its pathophysiological significance in advanced post-MI LV failure associated with type 2 diabetes remains unestablished. We thus hypothesized that an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV failure after MI in high-fat diet (HFD)-induced obese mice with type 2 diabetes. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 weeks. At 4 weeks of feeding, MI was created in mice by ligating left coronary artery. HFD-fed MI mice were treated with either apocynin or vehicle. HFD+MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7+/-0.1 vs. 5.3+/-0.2mm), end-diastolic pressure (EDP; 12+/-2 vs. 8+/-1mmHg) and lung weight/tibial length (10.1+/-0.3 vs. 8.7+/-0.7mg/mm) than ND+MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD+MI with apocynin significantly decreased LVEDD (5.4+/-0.1mm), LVEDP (9.7+/-0.8mmHg), lung weight/tibial length (9.0+/-0.3mg/mm), and concomitantly interstitial fibrosis of non-infarcted LV to ND+MI level without affecting body weight, glucose metabolism, and infarct size. NAD(P)H oxidase activity and O2(-) production were increased in non-infarcted LV tissues from HFD+MI, both of which were attenuated by apocynin to ND+MI level. Type 2 diabetes was associated with the exacerbation of LV failure after MI via increasing NAD(P)H oxidase-derived O2(-), which may be a novel important therapeutic target in advanced heart failure with diabetes. Key words: heart failure, diabetes, remodeling, antioxidants.