rusalatide-acetate and Chronic-Disease

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.

Topics: Angiogenesis Inducing Agents; Animals; Cell Hypoxia; Cells, Cultured; Chronic Disease; Coronary Angiography; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography, Stress; Endothelium, Vascular; Humans; Myocardial Ischemia; Myocardial Revascularization; Nitric Oxide; Nitric Oxide Synthase Type III; Peptide Fragments; Swine; Swine, Miniature; Thrombin; Vasodilation; Vasodilator Agents