Tags

Type your tag names separated by a space and hit enter

Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.
Free Radic Biol Med 2015; 87:137-47FR

Abstract

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.

Authors+Show Affiliations

Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Physiology, Monash University, Clayton, Victoria Australia 3004.Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.Experimental Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.Victor Chang Cardiac Research Institute, and University of New South Wales, Sydney New South Wales Australia 2010.Cardiac Hypertrophy, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004.Victor Chang Cardiac Research Institute, and University of New South Wales, Sydney New South Wales Australia 2010.Experimental Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria Australia 3004; Department of Medicine, Monash University, Clayton, Victoria Australia 3004.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25937176

Citation

De Blasio, Miles J., et al. "Therapeutic Targeting of Oxidative Stress With Coenzyme Q10 Counteracts Exaggerated Diabetic Cardiomyopathy in a Mouse Model of Diabetes With Diminished PI3K(p110α) Signaling." Free Radical Biology & Medicine, vol. 87, 2015, pp. 137-47.
De Blasio MJ, Huynh K, Qin C, et al. Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. Free Radic Biol Med. 2015;87:137-47.
De Blasio, M. J., Huynh, K., Qin, C., Rosli, S., Kiriazis, H., Ayer, A., ... Ritchie, R. H. (2015). Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. Free Radical Biology & Medicine, 87, pp. 137-47. doi:10.1016/j.freeradbiomed.2015.04.028.
De Blasio MJ, et al. Therapeutic Targeting of Oxidative Stress With Coenzyme Q10 Counteracts Exaggerated Diabetic Cardiomyopathy in a Mouse Model of Diabetes With Diminished PI3K(p110α) Signaling. Free Radic Biol Med. 2015;87:137-47. PubMed PMID: 25937176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. AU - De Blasio,Miles J, AU - Huynh,Karina, AU - Qin,Chengxue, AU - Rosli,Sarah, AU - Kiriazis,Helen, AU - Ayer,Anita, AU - Cemerlang,Nelly, AU - Stocker,Roland, AU - Du,Xiao-Jun, AU - McMullen,Julie R, AU - Ritchie,Rebecca H, Y1 - 2015/04/30/ PY - 2014/11/19/received PY - 2015/04/21/revised PY - 2015/04/22/accepted PY - 2015/5/5/entrez PY - 2015/5/6/pubmed PY - 2016/8/2/medline KW - Antioxidant KW - Cardiac fibrosis KW - Cardiomyocyte hypertrophy KW - Left ventricular function KW - Myocardium KW - NADPH oxidase KW - Reactive oxygen species KW - Superoxide KW - Type 1 diabetes SP - 137 EP - 47 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 87 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/25937176/Therapeutic_targeting_of_oxidative_stress_with_coenzyme_Q10_counteracts_exaggerated_diabetic_cardiomyopathy_in_a_mouse_model_of_diabetes_with_diminished_PI3K_p110α__signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(15)00191-4 DB - PRIME DP - Unbound Medicine ER -