Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts.
Diabetic patients are prone to metabolic perturbations that progressively contribute to structural, functional and proteomic alterations in the myocardium. Phosphodiesterase-5 (PDE-5) inhibitors exhibit cardioprotective effects against ischemic/reperfusion injury, however the effects of chronic administration of PDE-5 inhibitors, particularly under diabetic conditions, remain unknown. Hence, the present study was designed to identify novel protein targets related to long-acting PDE-5 inhibitor tadalafil-induced cardioprotection in diabetes. Using two-dimensional differential in-gel electrophoresis with 3 CyDye labeling and MALDI-TOF/TOF tandem mass spectrometry we identified alterations in the expressions of cardiac proteins in diabetic db/db mice treated with tadalafil. Tadalafil reversed the coordinated alterations of cytoskeletal/contractile proteins such as myosin light chain (MLY) 2 and 4, myosin heavy chain α and myosin-binding protein C which contributes to contractile dysfunction. The expression of intermediate filament protein vimentin and extra-cellular matrix proteins like cysteine and glycine rich protein-3 and collagen type VI α were upregulated in db/db mice indicating cardiac remodeling in diabetes. These detrimental proteomic alterations were reflected in cardiac function which were reversed in tadalafil treated mice. Tadalafil also enhanced antioxidant enzyme glutathione S-transferase Kappa-1 (GSKT-1) and downregulated redox regulatory chaperones like heat shock protein 8 (HSPA8), and 75 kD glucose regulatory protein (75GRP). Furthermore, tadalafil treatment significantly attenuated GSSG/GSH ratio and improved the metabolic status of db/db mice. Chronic treatment with tadalafil in db/db mice modulates proteins involved in cytoskeletal rearrangement and redox signaling of the heart, which may explain the beneficial effects of PDE-5 inhibition in diabetes.
Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA 23298-0204, USA.
Saisudha
S
Koka
Lei
L
Xi
Rakesh C
RC
Kukreja
D000818:Animals; D015153:Blotting, Western; D002243:Carbolines / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000068581:Tadalafil; D016277:Ventricular Function, Left / Q000187:drug effects*
D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil