Abstract 246: Adiporon, an Adiponectin Receptor Agonist, Inhibits P70s6kinase Signaling in Vascular Smooth Muscle Cells: Implications Toward Suppression of Injury-induced Neointima Formation in Mice

Background: Hypoadiponectinemia is closely correlated with insulin resistance and coronary artery disease. The use of exogenous adiponectin as a rational therapy to reduce cardiovascular disease risk has been hampered in a clinical setting due to its large molecular size and short plasma half-life. Recent studies demonstrate that Adiporon, a small molecule adiponectin receptor agonist, improves insulin resistance and glycemic control in type 2 diabetic mice. The present study is aimed at examining the likely regulatory effects of Adiporon on vascular smooth muscle cell (VSMC) phenotype. Methods: Using human aortic VSMCs, we examined the effects of AdipoRon (5 to 100 μM) on platelet-derived growth factor (PDGF, 30 ng/ml)-induced proliferative signaling events. In addition, we examined the effects of orally-administered AdipoRon (50 mg/kg/d) on injury-induced neointima formation in CJ57BL6 mice. Morphometric analysis of injured femoral artery was performed using H&E and EVG-stained sections. Results: Exposure of VSMCs to AdipoRon resulted in a significant decrease in PDGF-induced proliferation by ~63.8% and cyclin D1 expression by ~92.5% (n = 3). In addition, AdipoRon treatment led to significant diminutions in PDGF-induced phosphorylation of Akt, p70S6K, and its downstream targets that include 4E-BP1 and ribosomal protein S6, as revealed by immunoblot analysis (n = 3). Importantly, Adiporon administration (50mg/kg/d, PO) for three weeks led to a significant attenuation of neointima formation by ~63.7% in the injured femoral artery (n = 5-8). Conclusion: The present findings suggest that Adiporon (a small molecule adiponectin receptor agonist) may inhibit neointima formation after arterial injury by targeting p70S6K signaling in VSMCs. Future studies should investigate the likely vasoprotective effects of Adiporon in the mouse models of obesity and atherosclerosis.