title: Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1α signaling.
abstract: Enhanced nitric oxide (NO) production is known to activate silent information regulator 1 (SIRT1), which is a histone deacetylase that regulates PGC-1α, a regulator of mitochondrial biogenesis and coactivator of transcription factors impacting energy homeostasis. Since phosphodiesterase-5 inhibitors potentiate NO signaling, we hypothesized that chronic treatment with phosphodiesterase-5 inhibitor tadalafil would activate SIRT1-PGC-1α signaling and protect against metabolic stress-induced mitochondrial dysfunction in diabetic hearts. Diabetic db/db mice (n = 32/group; 40 wk old) were randomized to receive DMSO (10%, 0.2 ml ip) or tadalafil (1 mg/kg ip in 10% DMSO) for 8 wk. Wild-type C57BL mice served as nondiabetic controls. The hearts were excised and homogenized to study SIRT1 activity and downstream protein targets. Mitochondrial function was determined by measuring oxidative phosphorylation (OXPHOS), and reactive oxygen species generation was studied in isolated mitochondria. Tadalafil-treated diabetic mice demonstrated significantly improved left ventricular function, which is associated with increased cardiac SIRT1 activity. Tadalafil also enhanced plasma NO oxidation levels, myocardial SIRT1, PGC-1α expression, and phosphorylation of eNOS, Akt, and AMPK in the diabetic hearts. OXPHOS with the complex I substrate glutamate was decreased by 50% in diabetic hearts compared with the nondiabetic controls. Tadalafil protected OXPHOS with an improved glutamate state 3 respiration rates. The increased reactive oxygen species production from complex I was significantly decreased by tadalafil treatment. In conclusion, chronic treatment with tadalafil activates NO-induced SIRT1-PGC-1α signaling and attenuates mitochondrial dysfunction in type 2 diabetic hearts.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Saisudha
authors.initials: S
authors.lastname: Koka
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Hema S
authors.initials: HS
authors.lastname: Aluri
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Cardiology Section, Medical Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia; and Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia rakesh@vcu.edu.
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism; D000068581:Tadalafil; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002243:Carbolines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058986:Phosphodiesterase 5 Inhibitors; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D009569:Nitric Oxide; D000068581:Tadalafil; D056564:Sirtuin 1
keywords: OXPHOS; SIRT1; cardioprotection; nitric oxide; tadalafil; type 2 diabetes
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