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TP508 (Chrysalin^®) Reverses Endothelial Dysfunction and Increases Perfusion and Myocardial Function in Hearts With Chronic Ischemia

Michael E. DeBakey Institute, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas

Barbara Olszewska-Pazdrak, MD

Therapeutic Peptide Development Laboratory, Department of Biochemistry and Molecular Biology, the University of Texas Medical Branch, Galveston, Texas

Michelle M. Mertens, DVM

Michael E. DeBakey Institute, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas

Lori A. Makarski, DVM

Michael E. DeBakey Institute, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas

Matthew W. Miller, DVM, MS

Michael E. DeBakey Institute, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas

Travis W. Hein, PhD

Departments of Surgery and Ophthalmology, Scott and White Memorial Hospital, Temple, Texas

Lih Kuo, PhD

Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, Temple, Texas

Fred Clubb, DVM, PhD

Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas

Gerald M. Fuller, PhD

Department of Cell Biology, University of Alabama, Birmingham, Alabama

Darrell H. Carney, PhD

Therapeutic Peptide Development Laboratory, Department of Biochemistry and Molecular Biology, the University of Texas Medical Branch, Galveston, Texas, dcarney{at}utmb.edu

Endothelial dysfunction (ED) is characterized by impaired nitric oxide (NO) signaling, decreased NO-dependent vasodilatation, increased vascular inflammation, and diminished response to angiogenic factors. TP508 (Chrysalin^®), an angiogenic tissue repair peptide, was tested for potential effects on myocardial revascularization and ED using a porcine model of chronic myocardial ischemia. TP508 increased perfusion in ischemic regions up to16-fold (P < .02) and doubled myocardial wall thickening (P < .02) relative to placebo controls. Ischemic arterioles exhibited impaired NO-mediated vasodilation and diminished NO production. TP508 reversed ischemic effects, increasing NO-mediated vasodilation (P < .05), endothelial nitric oxide synthase (eNOS) expression, and NO production. In human endothelial cells, TP508 stimulated eNOS activation (1.84 ± 0.2-fold; P < .02), increased NO production (85 ± 18%; P < .02), and prevented hypoxia-induced eNOS downregulation (P < .01). Thus, TP508 reverses ED both in porcine ischemic hearts and cultured human endothelial cells. These results suggest potential therapeutic benefit of TP508 in myocardial revascularization and treatment of ED-related diseases.

Key Words: thrombin peptide TP508 • myocardial revascularization • endothelial dysfunction • nitric oxide • human coronary artery endothelial cells

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 13, No. 3, 214-225 (2008)
DOI: 10.1177/1074248408321468


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