title: Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway.
abstract: Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8(-/-) mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flow-mediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had favorable effects on hypertension treatment.
authors.affiliation: Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China. zhuzm@yahoo.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Peijian
authors.initials: P
authors.lastname: Wang
authors.forename: Shuangtao
authors.initials: S
authors.lastname: Ma
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Pu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Xiong
authors.forename: Daoyan
authors.initials: D
authors.lastname: Liu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002214:Capsules; D002478:Cells, Cultured; D003080:Cold Temperature; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D008610:Menthol / Q000494:pharmacology* / Q000627:therapeutic use; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D050053:TRPM Cation Channels / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002214:Capsules; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D002118:Calcium
keywords: TRPM8 protein, human; hypertension; menthol; muscle; rho-associated kinases; smooth, vascular; vasoconstriction