Background: Although hyperhomocysteinemia has long been recognized as an independent risk factor for vascular disease, the mechanisms of the pathogenesis of homocysteine are largely unknown. The objective of this study was to examine the effect of homocysteine on vasomotor function and endothelial integrity in intact porcine arteries.
Methods: Pig coronary artery rings were incubated with homocysteine (10, 50, or 100 microM) for 24 h. Myograph analysis was performed with thromboxane A2 analogue U46619 for contraction and bradykinin or sodium nitroprusside for relaxation. Pig carotid arteries were perfusion-cultured in control and 50 and 100 microM homocysteine treatment groups. The diameter change was analyzed in response to norepinephrine and acetylcholine, respectively. Endothelial morphology and nitric oxide synthase (eNOS) levels were determined by histology analysis.
Results: Endothelial-dependent vasorelaxation (bradykinin) was significantly reduced by 52, 87, and 97% in the pig coronary artery rings treated with 10, 50, and 100 microM homocysteine, respectively, compared to controls (P < 0.05). There were no differences in endothelium-independent vasorelaxation (sodium nitroprusside) or in smooth muscle contractility (U46619) between control and homocysteine-treated groups (P > 0.05). Acetylcholine-induced vasorelaxation was also significantly reduced by 44 and 98% in the pig carotid arteries treated with 50 and 100 microM homocysteine, respectively, compared to controls (P < 0.05). Variable degrees of endothelial cell injury, such as morphology change and detachment, were observed, and eNOS immunoreactivity was markedly reduced in both pig coronary and carotid arteries that were treated with high doses of homocysteine.
Conclusion: These data demonstrated that homocysteine significantly decreased endothelium-dependent vasorelaxation and eNOS immunoreactivity as well as induced marked endothelial injury in both porcine coronary and carotid arteries. This study suggests that homocysteine-mediated endothelial dysfunction and injury may play important roles in vascular lesion formation in the hyperhomocysteinemic patient.
(c)2001 Elsevier Science.