PT  - JOURNAL ARTICLE
AU  - Yun-Ping Mu
AU  - Da-Cen Lin
AU  - Si-Yi Zheng
AU  - Hai-Xia Jiao
AU  - James Sham
AU  - Mo-Jun Lin
TI  - Transient Receptor Potential Melastatin-8 Activation Induces Relaxation of Pulmonary Artery by Inhibition of Store-Operated Calcium Entry in Normoxic and Chronic Hypoxic Pulmonary Hypertensive Rats
AID  - 10.1124/jpet.117.247320
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.117.247320
4099  - http://jpet.aspetjournals.org/content/early/2018/04/05/jpet.117.247320.short
4100  - http://jpet.aspetjournals.org/content/early/2018/04/05/jpet.117.247320.full
AB  - Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). It is well established that store-operated Ca2+ entry (SOCE) is augmented in PASMCs during PH and it plays crucial roles in PH development. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) is down-regulated in PASMCs of PH animal models; and activation of TRPM8 causes relaxation of pulmonary arteries (PAs). However, the mechanism of TRPM8-induced PA relaxation is unclear. Here we examined the interaction of TRPM8 and SOCE in PAs and PASMCs of normoxic and chronic hypoxic pulmonary hypertensive (CHPH) rats, a model of human Group 3 PH. We found that TRPM8 was down-regulated and TRPM8-mediated cation entry was reduced in CHPH-PASMCs. Activation of TRPM8 with icilin caused concentration-dependent relaxation of cyclopiazonic acid (CPA) and ET-1 contracted endothelium-denuded PAs; and the effect was abolished by the SOCE antagonist Gd3+. Application of icilin to PASMCs suppressed CPA-induced Mn2+ quenching and Ca2+ entry, which was reversed by the TRPM8 antagonist AMTB. Moreover, the inhibitory effects of icilin on SOCE in PA and PASMCs of CHPH rats were significantly augmented due to enhanced SOCE activity in PH. Our results, therefore, demonstrated a novel mechanism of TRPM8-mediated inhibition of SOCE in pulmonary vasculature. Since SOCE is important for vascular remodeling and enhanced vasoconstriction, down-regulation of TRPM8 in PASMCs of CHPH rats may minimize its inhibitory influence to allow unimpeded SOCE activity for PH development.