Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes.
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 (O(2)(-)) 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 wk. At 4 wk of feeding, MI was created in mice by ligating the left coronary artery. HFD-fed MI mice were treated with either 10 mmol/l apocynin or vehicle. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 +/- 0.1 vs. 5.3 +/- 0.2 mm), end-diastolic pressure (12 +/- 2 vs. 8 +/- 1 mmHg), and lung weight/tibial length (10.1 +/- 0.3 vs. 8.7 +/- 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of noninfarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 +/- 0.1 mm), LV end-diastolic pressure (9.7 +/- 0.8 mmHg), lung weight/tibial length (9.0 +/- 0.3 mg/mm), and concomitantly interstitial fibrosis of noninfarcted LV to the ND + MI level without affecting body weight, glucose metabolism, and infarct size. NAD(P)H oxidase activity and O(2)(-) production were increased in noninfarcted LV tissues from HFD + MI, both of which were attenuated by apocynin to the ND + MI level. Type 2 diabetes was associated with the exacerbation of LV failure after MI via increasing NAD(P)H oxidase-derived O(2)(-), which may be a novel important therapeutic target in advanced heart failure with diabetes.
Matsushima
Shouji
S
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Kinugawa
Shintaro
S
Yokota
Takashi
T
Inoue
Naoki
N
Ohta
Yukihiro
Y
Hamaguchi
Sanae
S
Tsutsui
Hiroyuki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D004032:Diet; D004041:Dietary Fats; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000201:enzymology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D016019:Survival Analysis; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D001786:Blood Glucose; D003573:Cytochrome b Group; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D019255:NADPH Oxidases; C515614:Cyba protein, mouse