Ghrelin, a novel growth hormone–releasing peptide, is implicated to play a protective role in cardiovascular tissues. However, it is not clear whether ghrelin protects vascular tissues from injury secondary to risk factors such as homocysteine (Hcy). This study investigated the effect and potential mechanisms of ghrelin on Hcy-induced endothelial dysfunction.
Methods
Porcine coronary artery rings were incubated for 24 hours with ghrelin (100 ng/mL), Hcy (50 μM), or ghrelin plus Hcy. Endothelial vasomotor function was evaluated using the myograph tension model. The response to the thromboxane A2analog U46619, bradykinin, and sodium nitroprusside was analyzed. Endothelial nitric oxide synthase (eNOS) expression was determined using real-time polymerase chain reaction and immunohistochemistry staining, and superoxide anion production was documented lucigenin-enhanced chemiluminescence analysis. Human coronary artery endothelial cells (HCAECs) were treated with different concentrations of Hcy, ghrelin, or antighrelin receptor antibody for 24 hours, and eNOS protein levels were determined by Western blot analysis.
Results
Maximal contraction with U46619 and endothelium-independent vasorelaxation with sodium nitroprusside were not different among the four groups. However, endothelium-dependent vasorelaxation with bradykinin (10−6 M) was significantly reduced by 34% with Hcy compared with controls (P < .05). The addition of ghrelin to Hcy had a protective effect, with 61.6% relaxation, which was similar to controls (64.7%). Homocysteine significantly reduced eNOS expression, whereas ghrelin cotreatment effectively restored eNOS expression to the control levels. Superoxide anion levels, which were increased by 100% with Hcy, returned to control levels with ghrelin cotreatment. Ghrelin also effectively blocked the Hcy-induced decrease of eNOS protein levels in HCAECs in a concentration-dependent manner. Antighrelin receptor antibody effectively inhibited the effect of ghrelin.
Conclusion
Ghrelin has a protective effect in the porcine coronary artery by blocking Hcy-induced endothelial dysfunction, improving eNOS expression, and reducing oxidative stress. Ghrelin also shows a protective effect on HCACEs from the Hcy-induced decrease in eNOS protein levels. The effect of ghrelin is receptor-dependent. Thus, ghrelin administration may have beneficial effects in the treatment of vascular disease in patients with hyperhomocysteinemia.
Clinical Relevance
Homocysteine is an independent risk factor for atherosclerosis and other vascular lesions. It causes endothelial dysfunction and oxidative stress. Ghrelin, a novel growth hormone–releasing peptide, is implicated to play a protective role in cardiovascular tissues. This study investigated the effect and potential mechanisms of ghrelin on Hcy-induced endothelial dysfunction. The results showed that ghrelin has a protective effect in the porcine coronary artery and human coronary artery endothelial cells by blocking Hcy-induced endothelial dysfunction, improving endothelial nitric oxide synthase expression, and reducing oxidative stress. Ghrelin administration may have beneficial effects in the treatment of vascular disease in patients with hyperhomocysteinemia.
Cited by (0)
This work is partially supported by research grants from the National Institutes of Health (Yao, DE15543; Lin, HL076345; and Chen, HL65916, HL72716, and EB-002436), and from the Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Tex.
Competition of interest: none.
Currently, Dr Nasim Hedayati is at the Department of Surgery, University of California-Davis.
