title: Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure.
abstract: Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure. In this study, we used the Sugen5416/hypoxia/normoxia-induced PAH rat to determine whether altered pyridine nucleotide signaling in the failing heart contributes to 1) increased oxidative stress, 2) changes in metabolic phenotype, 3) autophagy, and 4) the PAH-induced failure. We found that increased reactive oxygen species, metabolic maladaptation, and autophagy contributed to the pathogenesis of right ventricular remodeling and hypertrophy that lead to left ventricular diastolic dysfunction. In addition, arterial elastance increased in PAH rats. Glucose-6-phosphate dehydrogenase is a major source of pyridine molecule (nicotinamide adenine dinucleotide phosphate), which is a substrate for nicotinamide adenine dinucleotide phosphate oxidases in the heart. Dehydroepiandrosterone, a 17-ketosteroid that reduces pulmonary hypertension and right ventricular hypertrophy, inhibited glucose-6-phosphate dehydrogenase, decreased oxidative stress, increased glucose oxidation and acetyl-coA, and reduced autophagy in the hearts of PAH rats. It also decreased arterial stiffness and improved left ventricular diastolic function. These findings demonstrate that pyridine nucleotide signaling, at least partly, mediates PAH-induced diastolic heart failure, and that reduction of glucose-6-phosphate dehydrogenase-derived nicotinamide adenine dinucleotide phosphate is beneficial to improve left ventricle diastolic function.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Dhawjbahadur K
authors.initials: DK
authors.lastname: Rawat
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Abdallah
authors.initials: A
authors.lastname: Alzoubi
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Rakhee
authors.initials: R
authors.lastname: Gupte
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Sukrutha
authors.initials: S
authors.lastname: Chettimada
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Makino
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Kahn
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Takao
authors.initials: T
authors.lastname: Okada
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.).
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (D.K.R., R.G., S.C., S.A.G.), Pharmacology (A.A., I.F.M.), Lung Biology (A.A., I.F.M., S.A.G.), Internal Medicine (I.F.M.), and Pathology (A.G.K.), University of South Alabama, College of Medicine, Mobile; and Department of Physiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan (M.W., T.O.). s_gupte@nymc.edu sachin_gupte@yahoo.com.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D054144:Heart Failure, Diastolic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
keywords: dehydroepiandrosterone; free radicals; heart function tests; lung