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Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation
Xiaohua Jiang1, Fan Yang, Hongmei Tan
1Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Arteriosclerosis, Thrombosis, and Vascular Biology
|October 8, 2005
Summary
High homocysteine levels impair blood vessel function by reducing nitric oxide production. This endothelial dysfunction is mainly caused by protein kinase C activation, contributing to cardiovascular disease risk.
Area of Science:
- Cardiovascular Biology
- Endothelial Function
- Metabolic Disease
Background:
- Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular disease.
- HHcy is linked to endothelial dysfunction, a key factor in vascular health.
Purpose of the Study:
- To investigate the mechanistic role of HHcy in endothelial dysfunction.
- To elucidate the molecular pathways affected by HHcy in the endothelium.
Main Methods:
- Utilized functional models: aortic rings and intravital microscopy in cystathionine beta-synthase null (CBS(-/-)) mice.
- Assessed endothelial nitric oxide synthase (eNOS) activity and phosphorylation in mouse and human aortic endothelial cells.
- Investigated the effect of a protein kinase C (PKC) inhibitor (GF109203X) on eNOS activity.
Main Results:
- Arterial relaxation was impaired in CBS(-/-) mice, while smooth muscle cell response to NO donors was preserved.
- HHcy significantly reduced eNOS activity and altered its phosphorylation status (increased Thr495) in endothelial cells.
- PKC inhibition reversed HHcy-induced eNOS inactivation and phosphorylation changes.
Conclusions:
- HHcy impairs endothelial function and eNOS activity.
- PKC activation is a primary mechanism underlying HHcy-mediated endothelial dysfunction.