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Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

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Abstract

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.

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Abbreviations

2D-DIGE:

Two-dimensional differential in-gel electrophoresis

ED:

Erectile dysfunction

CGRP-3:

Cysteine and glycine rich protein-3

EF-Tu:

Tu translational elongation factor

GSH:

Reduced glutathione

GSKT-1:

Glutathione S-transferase Kappa 1

GSSG:

Oxidised glutathione

HSPA8:

Heat shock protein 8

HMGB1:

High-mobility 553 group box 1

75GRP:

75 kD glucose related protein

MBP-C:

Myosin-binding protein C

αMHC:

Myosin heavy-chain α

MLY-2:

Myosin light chain 2

MLY-4:

Myosin light chain 4

NO:

Nitric oxide

PDE-5:

Phosphodiesterase-5

OPA:

o-phthalaldehyde

TAD:

Tadalafil

ROS:

Reactive oxygen species

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Acknowledgments

This work was supported by Grants from the National Institutes of Health (HL51045, HL79424, HL93685) to Rakesh C Kukreja. Saisudha Koka is supported by a postdoctoral fellowship from American Heart Association (11POST7400028). The authors acknowledge Dr. John Liao of Applied Biomics, Inc. for his excellent technical support in proteomic analysis.

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The authors declare that they have no conflict of interest.

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  1. 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 Koka, Lei Xi & Rakesh C. Kukreja

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  1. Saisudha Koka
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Correspondence to Rakesh C. Kukreja.

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Koka, S., Xi, L. & Kukreja, R.C. Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts. Basic Res Cardiol 107, 249 (2012). https://doi.org/10.1007/s00395-012-0249-5

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