Abstract
Endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. We tested the hypothesis that L-citrulline may ameliorate the endothelial function altered by ADMA in porcine coronary artery (PCA). Myograph study for vasorelaxation, electrochemical measurement for NO, RT-PCR, and Western blot analysis for expression of eNOS, argininosuccinate synthetase (ASS), and p-eNOSser1177 were performed. cGMP was determined by enzyme immunoassay. Superoxide anion (O2.−) production was detected by the lucigenin-enhanced chemiluminescence method. Compare with controls (96.03% ± 6.2%), the maximal relaxation induced by bradykinin was significantly attenuated (61.55% ± 4.8%, p < 0.01), and significantly restored by L-citrulline (82.67 ± 6.4%, p < 0.05) after 24 hours of ADMA exposure. Expression of eNOS, p-eNOSser1177, and ASS in PCA significantly increased after L-citrulline incubation. L-citrulline also markedly restored the NO production, and cGMP level which was reduced by ADMA. The increased O2.− production by ADMA was also inhibited by L-citrulline. L-citrulline restores the endothelial function in preparations treated with ADMA by preservation of NO production and suppression of O2.− generation. Preservation of NO is attributed to the upregulation of eNOS expression along with activation of p-eNOSser1177. L-citrulline improves endothelium-dependent vasodilation through NO/ cGMP pathway.
Highlights
Nitric oxide (NO) plays an important role in the maintenance of vascular tone and structure
Present study has demonstrated in porcine coronary artery (PCA) that 1) L-citrulline prevents Asymmetric dimethylarginine (ADMA)-induced endothelial dysfunction with restoration of NO production; 2) the mechanisms underlying the protective effect of L-citrulline against ADMA include upregulation of Endogenous nitric oxide synthase (eNOS) expression and enhancement of eNOS activation, upregulation of Argininosuccinate synthetase (ASS) expression, and inhibition of O2.− production
3) NO/cGMP pathway is involved in the endothelial protection of L-citrulline
Summary
Nitric oxide (NO) plays an important role in the maintenance of vascular tone and structure. By competing with L-arginine, ADMA suppresses the activity of eNOS, causing low expression of NO resulting in endothelial dysfunction[1]. ADMA correlates with vascular superoxide generation, and acts as an independent predictor of it[2] Superoxide anion (O2.−) can reduce NO bioavailability and cause endothelial dysfunction[3,4]. Endothelial dysfunction is a common mechanism which several cardiovascular risk factors mediate their deleterious effects on the vascular relaxation[5,6,7]. Studies have indicated oral supplementation of L-citrulline could upregulate eNOS expression, offering endothelium protection in animal models[10,11]. The present study was designed to evaluate the protection effect of L-citrulline on ADMA– induced injury of endothelium dependent relaxation in porcine coronary artery (PCA) and further reveal relevant mechanisms. Our findings may provide new insights in the protection of the coronary artery endothelium
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