TP508 (Chrysalin®) reverses endothelial dysfunction and increases perfusion and myocardial function in hearts with chronic ischemia

被引:15
作者
Fossum, Theresa W. [2 ]
Olszewska-Pazdrak, Barbara [1 ]
Mertens, Michelle M. [2 ]
Makarski, Lori A. [2 ]
Miller, Matthew W. [2 ]
Hein, Travis W. [3 ,4 ]
Kuo, Lih [5 ]
Clubb, Fred [6 ]
Fuller, Gerald M. [7 ]
Carney, Darrell H. [1 ]
机构
[1] Univ Texas Med Branch, Therapeut Peptide Dev Lab, Dept Biochem & Mol Biol, Galveston, TX 77555 USA
[2] Texas A&M Univ, Coll Vet Med, Michael E DeBakey Inst, Dept Small Anim Clin Sci, College Stn, TX 77843 USA
[3] Scott & White Mem Hosp & Clin, Dept Surg, Temple, TX 76508 USA
[4] Scott & White Mem Hosp & Clin, Dept Ophthalmol, Temple, TX 76508 USA
[5] Texas A&M Hlth Sci Ctr, Dept Syst Biol & Translat Med, Temple, TX USA
[6] Texas A&M Univ, Coll Vet Med, Dept Pathobiol, College Stn, TX 77843 USA
[7] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
关键词
thrombin peptide TP508; myocardial revascularization; endothelial dysfunction; nitric oxide; human coronary artery endothelial cells;
D O I
10.1177/1074248408321468
中图分类号
R5 [内科学];
学科分类号
1002 [临床医学]; 100201 [内科学];
摘要
Endothelial dysfunction (ED) is characterized impaired nitric oxide (NO) signaling, decreased NO-dependent vasodilatation, increased vascular inflammation, and diminished response to angiogenic factors. TP508 (Chrysalin (R)), 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 to 16-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 down regulation (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.
引用
收藏
页码:214 / 225
页数:12
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