Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.
Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and β-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure.
Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.
Miles J
MJ
De Blasio
Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Physiology, Monash University, Clayton, Victoria Australia 3004.
Karina
K
Huynh
Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.
Chengxue
C
Qin
Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.
Sarah
S
Rosli
Experimental Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.
Helen
H
Kiriazis
Victor Chang Cardiac Research Institute, and University of New South Wales, Sydney New South Wales Australia 2010.
Anita
A
Ayer
Cardiac Hypertrophy, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.
Nelly
N
Cemerlang
Victor Chang Cardiac Research Institute, and University of New South Wales, Sydney New South Wales Australia 2010.
Roland
R
Stocker
Experimental Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Medicine, Monash University, Clayton, Victoria Australia 3004.
Xiao-Jun
XJ
Du
Department of Physiology, Monash University, Clayton, Victoria Australia 3004; Cardiac Hypertrophy, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Medicine, Monash University, Clayton, Victoria Australia 3004.
Julie R
JR
McMullen
Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Medicine, Monash University, Clayton, Victoria Australia 3004. Electronic address: rebecca.ritchie@bakeridi.edu.au.
Rebecca H
RH
Ritchie
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000975:Antioxidants; D014451:Ubiquinone; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; C024989:coenzyme Q10
Antioxidant; Cardiac fibrosis; Cardiomyocyte hypertrophy; Left ventricular function; Myocardium; NADPH oxidase; Reactive oxygen species; Superoxide; Type 1 diabetes