AICAR‐induced vasorelaxation is associated with the phosphorylation of HspB6 and VASP

Abstract

AMP-activated protein kinase(AMPK) is a major regulator of metabolism and pharmacological regulation of this kinase has been widely used in the treatment of diabetes. Heat shock protein B6 (HspB6) and vasodilator-stimulated phosphoprotein (VASP) modulates thin filament regulation of vascular smooth muscle tone. This study examined the role of HspB6 in the AMPK-induced signaling pathways that lead to enhanced vasorelaxation in rat thoracic aorta (RA). Endothelium intact or denuded RA rings were either pre-contracted with phenylephrine (PE) and treated with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) to induce relaxation, or incubated with AICAR prior to vasocontraction by PE. Force was measured in a muscle bath and tissues were frozen under tension. AICAR induced relaxation in PE pre-contracted tissues and pretreatment of RA rings with AICAR inhibited PE-induced contraction. Treatment with L-NAME prior to AICAR treatment partially abolished the effects of AICAR. Both AICAR-induced vasorelaxation and inhibition of contraction were associated with increased phosphorylation of HspB6 at Ser16 and VASP. These data show that activation of AMPK leads to vasorelaxation via endothelial and smooth muscle dependent mechanisms and is associated with the phosphorylation of HspB6 and VASP. This modulation may have potential implication in diabetic vascular disorders. Supported by NIH grant.