title: TRPM8 downregulation by angiotensin II in vascular smooth muscle cells is involved in hypertension.
abstract: Angiotensin II (Ang II)-induced injury of vascular smooth muscle cells (VSMCs) serves an important role in hypertension and other cardiovascular disorders. Transient receptor potential melastatin 8 (TRPM8) is a thermally‑regulated Ca2+‑permeable channel that is activated by reduced body temperature. Although several recent studies have revealed the regulatory effect of TRPM8 in vascular tone and hypertension, the precise role of TRPM8 in dysfunction of vascular smooth muscle cells (VSMCs) induced by Ang II remains elusive. In the present study, the possible function of TRPM8 in Ang II‑induced VSMCs malfunction in vivo and in vitro was investigated. In the aortae from rats that had undergone a two‑kidney one‑clip operation, which is a widely‑used renovascular hypertension model, the mRNA and protein levels of TRPM8 were reduced. In addition, exogenous Ang II treatment decreased TRPM8 mRNA and protein expression levels in primary cultures of rat VSMCs. TRPM8 activation by menthol, a pharmacological agonist, in VSMCs, significantly attenuated the Ang II‑induced increase in reactive oxygen species and H2O2 production. In addition, TRPM8 activation reduced the Ang II‑induced upregulation of NADPH oxidase (NOX) 1 and NOX4 in VSMCs. Furthermore, TRPM8 activation relieved the Ang II‑induced activation of ras homolog gene family, member A‑rho associated protein kinase 2 and janus kinase 2 signaling pathways in VSMCs. In conclusion, the results presented in the current study indicated that TRPM8 downregulation by Ang II in VSMCs may be involved in hypertension.
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China.
authors.forename: Jing-Ming
authors.initials: JM
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China.
authors.forename: Dong-Jie
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Shen
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D015536:Down-Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1