Homocysteine‐induced atherogenesis involves collagen remodeling via AT1 receptor up regulation

Numerous efforts have been made during the last decades but many questions related to etiology of atherosclerosis remain unanswered. Hyperhomocysteinemia (HHcy) is a known risk factor for atherosclerosis however the precise molecular mechanisms of HHcy‐induced atherosclerotic lesion formation are poorly understood. In the present study we investigated whether HHcy‐induced collagen deposition secondary to Agniotensin II type 1 (AT1) receptor up regulation leads to atherosclerosis in vascular tissue. Incubation of endothelial cells with HHcy, dose and time‐dependently increase AT1 receptor expression. AT1 receptor up regulation was found to phosphorylate mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). In addition to that, increased synthesis and deposition of collagen was observed in the matrix. AT1 blocker losartan inhibited MAPK and STAT3 phosphorylation and attenuated collagen deposition in HHcy‐induced cultured medium suggesting the possible pathway of collagen remodeling. Free radical scavenger NAC (N‐Acetyl‐Cysteine), down regulated HHcy‐induced AT1 expression and AT1 related MAPK and STAT3 phosphorylation as well as collagen deposition. Our results suggest that HHcy‐induced vascular remodeling of collagen deposition occurs through modulation of AT1 receptor and MAPK and STAT3 activation. Supported in part by NIH and AHA grants