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Impaired nitric oxide-mediated flow-induced coronary dilation in hyperhomocysteinemia: morphological and functional
Zoltan Ungvari1, Anna Csiszar, Zsolt Bagi
1Department of Pathophysiology, Semmelweis University, Budapest, Hungary.
Insights
High homocysteine levels impair coronary artery function by reducing nitric oxide availability, contributing to heart disease risk. This study reveals how oxidative stress underlies these effects.
Area of Science:
- Cardiovascular Science
- Vascular Biology
- Biochemistry
Background:
- Hyperhomocysteinemia (HHcy) is a risk factor for myocardial infarction.
- The impact of HHcy on endothelium-dependent coronary artery dilation remains unclear.
Purpose of the Study:
- To investigate the effect of HHcy on endothelium-dependent flow-induced dilation in coronary arteries.
- To elucidate the mechanisms underlying impaired vascular function in HHcy.
Main Methods:
- Small intramural coronary arteries from control and HHcy rats were studied using videomicroscopy.
- Nitric oxide synthase inhibition, NO donor administration, and antioxidant treatments were employed.
- Superoxide production and protein nitrosation were assessed.
Main Results:
- Flow-induced dilation was absent in HHcy coronary arteries.
- HHcy arteries showed impaired nitric oxide-mediated responses, but responded to NO donors.
- Superoxide dismutase restored flow-induced dilation in HHcy arteries, indicating a role for oxidative stress.
- Increased superoxide production and peroxynitrite formation (indicated by nitrotyrosine) were observed in HHcy coronaries.
Conclusions:
- HHcy impairs flow-induced coronary artery dilation by scavenging nitric oxide with superoxide, forming peroxynitrite.
- This peroxynitrite formation leads to protein nitrosation and reduced nitric oxide bioavailability.
- These vascular dysfunctions may contribute to atherosclerosis and ischemic heart disease development.
Abstract:
Hyperhomocysteinemia (HHcy) is a newly recognized risk factor for myocardial infarction, however, the effect of HHcy on endothelium-dependent flow-induced dilation of coronary arteries is not known. Thus, changes in diameter of small intramural coronary arteries (diameter, approximately 145 microm) isolated from control rats and rats with methionine diet-induced HHcy were investigated by videomicroscopy. Increases in intraluminal flow (from 0 to 40 microl/min) elicited dilations of control vessels (maximum, 25 +/- 2 microm), responses that were absent in HHcy arteries. The nitric oxide (NO) synthase inhibitor L-NAME inhibited flow-induced dilation of control coronaries, whereas it had no effect on responses of HHcy arteries. Dilations of control and HHcy arteries to the NO donor sodium nitroprusside were not different. Responses to flow in HHcy coronary arteries were unaffected by administration of L-arginine or the prostaglandin H(2)/thromboxane A(2) receptor antagonist SQ 29,548. However, in the presence of superoxide dismutase (plus catalase) or the superoxide scavenger Tiron increases in flow elicited L-NAME-sensitive dilations of HHcy coronaries (maximum, 18 +/- 5 microm). Also, superoxide dismutase significantly reduced the enhanced superoxide production of HHcy coronaries (measured by the lucigenin chemiluminescence method). Single vessel Western blotting showed an increased tyrosine nitrosation (a stable biomarker of tissue peroxynitrite formation) in HHcy coronaries. Also, extensive prevalence of 3-nitrotyrosine immunoreactivity was observed in HHcy coronaries that was confined primarily to the subendothelial layers of smooth muscle. We propose that in HHcy an increased level of superoxide scavenges NO forming peroxynitrite, which increases protein nitrosation. The reduced bioavailability of NO impairs flow-induced dilations of coronary arteries, which may contribute to the development of coronary atherosclerosis and ischemic heart disease.