| First Author | Jiang X | Year | 2005 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 25 |
| Issue | 12 | Pages | 2515-21 |
| PubMed ID | 16210565 | Mgi Jnum | J:116854 |
| Mgi Id | MGI:3695109 | Doi | 10.1161/01.ATV.0000189559.87328.e4 |
| Citation | Jiang X, et al. (2005) Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler Thromb Vasc Biol 25(12):2515-21 |
| abstractText | OBJECTIVE: A risk factor for cardiovascular disease, hyperhomocystinemia (HHcy), is associated with endothelial dysfunction. In this study, we examined the mechanistic role of HHcy in endothelial dysfunction. METHODS AND RESULTS: Through the use of 2 functional models, aortic rings and intravital video microscopy of the cremaster, we found that arterial relaxation in response to the endothelium-dependent vessel relaxant, acetylcholine or the nitric oxide synthase (NOS) activator (A23187), was significantly impaired in cystathionine beta-synthase null (CBS(-/-)) mice. However, the vascular smooth muscle cell (VSMC) response to the nitric oxide (NO) donor (SNAP) was preserved in CBS(-/-) mice. In addition, superoxide dismutase and catalase failed to restore endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) activity was significantly reduced in mouse aortic endothelial cells (MAECs) of CBS(-/-) mice, as well as in Hcy-treated mouse and human aortic endothelial cells (HAECs). Hcy-mediated eNOS inhibition--which was not rescued by adenoviral transduction of superoxide dismutase and glutathione peroxidase, or by tetrahydrobiopterin, sepiapterin, and arginine supplementations in MAEC--was associated with decreased protein expression and increased threonine 495 phosphorylation of eNOS in HAECs. Ultimately, a protein kinase C (PKC) inhibitor, GF109203X (GFX), reversed Hcy-mediated eNOS inactivation and threonine 495 phosphorylation in HAECs. CONCLUSIONS: These data suggest that HHcy impairs endothelial function and eNOS activity, primarily through PKC activation. |
