Nitrative Stress in Cerebral Endothelium is Mediated by mGluR5 in Hyperhomocysteinemia

摘要: Hyperhomocysteinemia (HHcy) disrupts nitric oxide (NO) signaling and increases nitrative stress in cerebral microvascular endothelial cells (CMVECs). This is mediated, part, by protein nitrotyrosinylation (3-nitrotyrosine; 3-NT) though the mechanisms which extracellular homocysteine (Hcy) generates intracellular 3-NT are unknown. Using a murine model of mild HHcy (cbs+/− mouse), we show that significantly elevated microvessels with concomitant reductions serum NO bioavailability as compared wild-type littermate controls (cbs+/+). Directed pharmacology identified receptor-dependent mechanism for formation CMVECs. Homocysteine increased expression inducible synthase (iNOS) 3-NT, both were blocked inhibition metabotropic glutamate receptor-5 (mGluR5) specific antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride. Activation mGluR5 sufficient necessary to drive because direct activation using mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine also iNOS while knockdown receptor short hairpin RNA (shRNA) their increase response Hcy. Nitric derived from was required Hcy-mediated effect 1400W. These results provide first evidence process explains how plasma Hcy levels control endothelium.