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Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH.
Am J Physiol Heart Circ Physiol 2009; 297(1):H153-62AJ

Abstract

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O(2)(-))] and the mechanisms underlying O(2)(-) production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O(2)(-) and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O(2)(-) generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9-11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased (P < 0.05). O(2)(-) levels were elevated (70-90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91(ds-tat) (50 microM) or by the mitochondrial respiratory chain inhibitors antimycin (10 microM) and rotenone (50 microM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 microM) also reduced (P < 0.05) O(2)(-) production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole (P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O(2)(-) generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O(2)(-) production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.

Authors+Show Affiliations

Department of Physiology, New York Medical College, Valhalla, NY, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19429815

Citation

Serpillon, Sabrina, et al. "Superoxide Production By NAD(P)H Oxidase and Mitochondria Is Increased in Genetically Obese and Hyperglycemic Rat Heart and Aorta Before the Development of Cardiac Dysfunction. the Role of Glucose-6-phosphate Dehydrogenase-derived NADPH." American Journal of Physiology. Heart and Circulatory Physiology, vol. 297, no. 1, 2009, pp. H153-62.
Serpillon S, Floyd BC, Gupte RS, et al. Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol. 2009;297(1):H153-62.
Serpillon, S., Floyd, B. C., Gupte, R. S., George, S., Kozicky, M., Neito, V., ... Gupte, S. A. (2009). Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. American Journal of Physiology. Heart and Circulatory Physiology, 297(1), pp. H153-62. doi:10.1152/ajpheart.01142.2008.
Serpillon S, et al. Superoxide Production By NAD(P)H Oxidase and Mitochondria Is Increased in Genetically Obese and Hyperglycemic Rat Heart and Aorta Before the Development of Cardiac Dysfunction. the Role of Glucose-6-phosphate Dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol. 2009;297(1):H153-62. PubMed PMID: 19429815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. AU - Serpillon,Sabrina, AU - Floyd,Beverly C, AU - Gupte,Rakhee S, AU - George,Shimran, AU - Kozicky,Mark, AU - Neito,Venessa, AU - Recchia,Fabio, AU - Stanley,William, AU - Wolin,Michael S, AU - Gupte,Sachin A, Y1 - 2009/05/08/ PY - 2009/5/12/entrez PY - 2009/5/12/pubmed PY - 2009/8/13/medline SP - H153 EP - 62 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 297 IS - 1 N2 - Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O(2)(-))] and the mechanisms underlying O(2)(-) production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O(2)(-) and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O(2)(-) generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9-11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased (P < 0.05). O(2)(-) levels were elevated (70-90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91(ds-tat) (50 microM) or by the mitochondrial respiratory chain inhibitors antimycin (10 microM) and rotenone (50 microM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 microM) also reduced (P < 0.05) O(2)(-) production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole (P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O(2)(-) generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O(2)(-) production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/19429815/Superoxide_production_by_NAD_P_H_oxidase_and_mitochondria_is_increased_in_genetically_obese_and_hyperglycemic_rat_heart_and_aorta_before_the_development_of_cardiac_dysfunction__The_role_of_glucose_6_phosphate_dehydrogenase_derived_NADPH_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.01142.2008?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -