Adipocytokine, progranulin, augments acetylcholine-induced nitric oxide-mediated relaxation through the increases of cGMP production in rat isolated mesenteric artery.

Abstract

Progranulin (PGRN) is a novel adipocytokine with anti-inflammatory effects in vascular cells. The aim of this study was to clarify the effects of PGRN on reactivity of isolated blood vessel. Isometric contraction of rat isolated superior mesenteric artery was measured. Pre-treatment with PGRN (10-100ngmL-1 , 30min) had no effect on noradrenaline- or 5-hydroxytriptamine-induced contraction. On the other hand, pre-treatment with PGRN (100ngmL-1 ) augmented acetylcholine (ACh; 30nm)-induced endothelium-dependent relaxation. Pre-treatment with PGRN (100ngmL-1 ) augmented ACh (10μm)-induced nitric oxide (NO)-mediated relaxation in the presence of indomethacin (10μm), a cyclooxygenase inhibitor, and tetraethyl ammonium (10mm), a non-selective potassium channel blocker. In contrast, pre-treatment with PGRN (100ngmL-1 ) had no effect on ACh-induced endothelium-derived hyperpolarizing factor-mediated relaxation. Pre-treatment with PGRN (100ngmL-1 ) had no effect on ACh (10μm, 1min)-induced endothelial NO synthase phosphorylation (at Ser1177) as determined by Western blotting. Pre-treatment with PGRN (100ngmL-1 ) augmented an NO donor, sodium nitroprusside (SNP; 30nm-1μm)- but not a membrane-permeable cGMP analogue, 8-bromo-cGMP-induced relaxation. In the presence of 3-isobutyl-1-methylxanthine (100μm), a phosphodiesterase inhibitor, pre-treatment with PGRN (100ngmL-1 ) increased SNP (30nm, 5min)-induced cGMP production as determined by enzyme immunoassay. We for the first time demonstrate that PGRN augments ACh-induced NO-mediated relaxation through the increases of cGMP production in smooth muscle. These results indicate PGRN as a possible pharmacotherapeutic target against cardiovascular diseases including obesity-related hypertension.