Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation.

Abstract

Retinol-binding protein 4 (RBP4) is a newly discovered adipocytokine related to insulin resistance (IR). Hyperinsulinemia and IR are the major risk factors for cardiovascular diseases (CVD). The role of RBP4 in CVD has not yet been determined. The present study was designed to analyze the correlation of RBP4 and CVD risk factors and to evaluate the role of RBP4 in proliferation of vascular smooth muscle cells during hyperinsulinemia and the underlying mechanisms. Plasma RBP4 concentration, IR-related indexes, and cardiovascular risk factors were measured from blood samples of hyperinsulinemic rats (HIns) and control SD rats (Cons). The vascular morphology and the expression of ERK1/2, p-ERK1/2 in arterial tissues of rats were assessed. Different concentrations of RBP4 (1, 4 μg/ml) were used as intervention factor during insulin-induced aortic smooth muscle cells (RASMCs) proliferation. The expression of cell growth signaling pathways was assessed to identify the active pathway during this proliferation. Specifically, ERK1/2 inhibitor PD98059 and JAK2 inhibitor AG490 were used to detect it. RBP4 expression was higher in HIns compared with Cons (p < 0.01). Plasma RBP4 concentrations were positively correlated with TG (r = 0.490), hsCRP (r = 0.565), media thickness (r = 0.890), and p-ERK1/2 protein (r = 0.746) (p < 0.05 each). In cultured RASMCs, RBP4 enhanced insulin-induced proliferation of cells and expression of p-ERK1/2 and p-JAK2. Blockade of ERK1/2 signaling pathway inhibited RBP4-induced proliferation of RASMCs, while suppressing JAK2 remains unchanged. These results suggest that plasma RBP4 concentrations were associated with CVD. In addition, RBP4 increases the proliferation of VSMCs induced by hyperinsulinism via activation of MAPK signaling pathway.