Short homologous peptides based on C-terminal sequences of fibrinogen β- and γ-chains (Haptides) affect cardiovascular function by eNOS inhibition.
Haptides are a family of 19-21-mer cell-binding and permeating peptides homologous to sequences in the C termini on both fibrinogen β- and γ-chain (Cβ and preCγ, respectively). The effect of the Haptides on the cardiovascular system was studied by different assays, including the activity of isolated perfused rat heart and blood vessels in the organ bath. Haptides (50-80 μg/ml) decreased the hemodynamic functions of perfused rat hearts by up to 60% (p < 0.05) in a dose-dependent manner. Whole fibrinogen or a control nonrelated peptide (Cα) did not show such an effect. The NO donor, sodium nitroprusside, reversed the inhibitory effects of Haptides. L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, did not further augment the effect of the Haptides. Perfused (FITC)Haptides were attached to the coronary endothelium. In myocardial homogenates and HUVEC, Haptides significantly decreased eNOS activity, but had no effect on the contraction of isolated cultured adult cardiomyocytes. Haptides also significantly enhanced the contraction of rings of rat aorta and human mammary artery vessels ex vivo only when the endothelium was intact. Haptides seem to affect the coronary endothelium, but not the cardiomyocytes, by inhibiting eNOS activity, causing vasoconstriction, temporary ischemia and impaired myocardial function that seem to be related to the amino acid composition of the Haptides.
Basheer
Maamoun
M
Laboratory of Biotechnology and Radiobiology, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Schwalb
Herzl
H
Gilon
Dan
D
Doviner
Victoria
V
Sherman
Yoav
Y
Shapira
Oz M
OM
Gorodetsky
Raphael
R
D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005340:Fibrinogen / Q000737:chemistry / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010477:Perfusion; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010455:Peptides; D009569:Nitric Oxide; D005340:Fibrinogen; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat