Submitted on December 24, 2008
Revised on May 15, 2009
Accepted on May 21, 2009
Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of post-infarct heart failure in type 2 diabetes
Shouji Matsushima1, Shintaro Kinugawa1*, Takashi Yokota2, Naoki Inoue1, Yukihiro Ohta1, Sanae Hamaguchi1, and Hiroyuki Tsutsui1
1 Hokkaido University
2 Hokkaido University Graduate School of Medicine
* To whom correspondence should be addressed. E-mail: tuckahoe{at}med.hokudai.ac.jp.
Type 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.
