RAGE Critically Mediates Post-injury Carotic Artery Vascular Remodeling By Regulation Of Mpk Actiyity Via LKB1and PP2A

Objective:Vascular remodeling involves smooth muscle cell (SMC) proliferation and migration that drives neointima formation and ultimate arterial stenosis, thrombosis, and ischemia in cardiovascular disease such as atherosclerosis, hypertension, and arterial revascularization. RAGE is a transmembrane signaling receptor implicated in diabetic renal and vascular complications, and known to drive vascular remodeling after injury. AMPK is a metabolic super-regulator that modulates cell differentiation. AMPK activation inhibits SMC proliferation and vascular remodeling, and exerts anti-inflammatory effects. Regulation of AMPK involves phosphorylation by upstream kinases and decreased phosphorylation by protein phosphatases. LKB1, a serine/threonine protein kinase that was first identified as a tumor suppressor, is the major upstream kinase activating AMPK. Protein phosphatase2A (PP2A) inactivates AMPK by de-phosphorylation of AMPK. Here, we tested the hypothesis that RAGE promotes vascular remodeling by modulating AMPK, and specificallyt through regulation of LKB1and PP2A. Methods and Results:We studied RAGE ligands known to increase in diseased arteries and to mediate diabetic and atherosclerotic vascular disease (the S100calgranulin S100A11, and glycated albumin).6-8weeks old WT and Rage-/-mice were used for carotid artery ligation. S100A11and glycated albumin induced decreased AMPK activity in conjunction with increased proliferation and migration of cultured SMCs, effects inhibited by both RAGE deficiency and prior AMPK activation. In siRNA studies, LKB1and PP2A were demonstrated to critically regulate AMPK activity in SMCs. Expression of RAGE and S100A11increased following murine carotid artery ligation, but AMPK activity, and LKB and PP2A phosphorylation, decreased in situ. Last, neointima formation was attenuated in Rage-/-mice, in conjunction with increased in situ LKB1and PP2A phosphorylation and increased AMPK activity, demonstrated by tissue Western blotting and immunohistochemistry.Conclusion:RAGE promotes vascular remodeling after arterial injury by promoting decreased AMPK-phosphorylating LKB1activity and increased AMPK-dephosphorylating PP2A activity, thereby suppressing AMPK activation. Increasing AMPK activity is a novel potential approach to diseases of vascular remodeling.