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Abstract
Obesity is associated with insulin resistance and an increase in the risk of cardiovascular disease, including atherosclerosis, restenosis after angioplasty, and hypertension. Adiponectin, one of the key adipokines released from adipose tissue, functions as an insulin sensitizer with anti-inflammatory and vasoprotective properties. Hypoadiponectinemia seen in obesity and type 2 diabetes is closely correlated with the development of vascular disease. Administration of adiponectin as a rational therapy is not practically feasible in a clinical setting due to its short half-life and high molecular mass. Alternative strategies may therefore include upregulation and/or activation of adiponectin receptors (AdipoR). Recently, Okada-Iwabu et al. reported the first orally active small-molecule AdipoR agonist, AdipoRon. It binds to and activates AdipoR1 and AdipoR2 subtypes leading to the activation of AMP-activated protein kinase (AMPK) and PPAR- signaling pathways in liver and skeletal muscle. In high fat diet-fed mice, AdipoRon ameliorates insulin resistance, lowers plasma glucose level, increases fatty acid oxidation, and reduces oxidative stress, suggesting that AdipoRon is a viable treatment option for vascular disease. The present study is aimed at examining the likely beneficial effects of AdipoRon in the vessel wall. Oral administration of AdipoRon (50 mg/Kg) in C57BL/6J mice significantly diminished arterial injury-induced neointima formation in vivo. Under in vitro conditions, AdipoRon treatment led to a significant inhibition of platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (VSMC) proliferation. From a mechanistic standpoint, AdipoRon enhanced AMPK activation and diminished basal and PDGF-induced phosphorylation of mTOR and its downstream targets, including p70S6K/S6 and 4E-BP1 in VSMCs. However, siRNA-mediated AMPK downregulation resulted in persistent inhibition of p70S6K/S6 phosphorylation, suggesting AMPK-independent effects for AdipoRon inhibition of mTOR signaling. Furthermore, in ex vivo studies using endothelium-denuded rat aorta, AdipoRon treatment led to an increase in AMPK phosphorylation with an accompanying decrease in agonist-induced smooth muscle contractility. Pretreatment with compound C (an AMPK inhibitor) did not affect AdipoRon inhibition of smooth muscle contractility, suggesting that AMPK activation does not contribute to AdipoRon-mediated vasorelaxant response. Together, the present findings suggest that the orally-administered AdipoRon has the potential to limit restenosis after angioplasty and promote vasodilation independent of AMPK activation in insulin-resistant state.