INHIBITORY EFFECT OF D3 DOPAMINE RECEPTORS ON INSULIN RECEPTOR EXPRESSION AND FUNCTION IN VASCULAR SMOOTH MUSCLE CELLS: PP.13.472

Abstract

Vascular smooth muscle cell (VSMC) proliferation, which is central to development of vascular diseases, including hypertension, is regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates the VSMC proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMC proliferation (Am J Physiol Heart Circ Physiol. 2008;294:H2761-8). We hypothesize that there is an interaction between D3 dopamine and insulin receptors in VSMCs; stimulation of D3 receptor inhibits insulin receptor expression and function. We found that stimulation of the D3 dopamine receptor inhibited the insulin receptor expression in a concentration- and time-dependent manner in rat aortic A10 cells, an embryonic thoracic aortic smooth muscle cells from normotensive Berlin-Druckrey IX. The inhibitory effect was evident at 10–7 M, noted as early as 2 hrs and maintained for at least 30rs. The inhibitory effect of D3 receptor on VSMC proliferation was blocked by PKA inhibitor (PKA inhibitor 14–22, 10–6 M), indicating that PKA is involved into the signal pathway. There is a physiological significance of the interaction between D3 receptor and insulin receptors because the D3 receptor agonist, PD128907, by itself had no effect on VSMC proliferation, but reduced the stimulatory effect of insulin VSMC proliferation, determined by MTT assay (control = 0.3±0.004, 10–7 M insulin = 0.6±0.007; 10–7 M PD128907 + 10–7 M insulin = 0.4±0.01, P < 0.05, n = 9). The inhibitory effect of D3 receptor on insulin receptor expression and function also occurred in primary cultured VSMCs from Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) (WKY: control = 0.3±0.01, 10–7 M insulin = 0.6±0.01; 10–7 M PD128907 + 10–7 M insulin = 0.4±0.01; SHR: control = 0.3±0.03, 10–7 M insulin = 0.7±0.02; 10–7 M PD128907 + 10–7 M insulin = 0.5±0.05, P < 0.05, n = 5). We suggest that the inhibitory effect of the D3 receptor on insulin receptor expression and function may be an alternative to reduce the effect of insulin in hypertension.