The role of the Ca^(2+)-permeable ion channel TRPC5 in regulating vasocontraction in obesity is poorly understood.Here,we investigated whether TRPC5 contributes to vascular dysfunction in obesity by promoting endothel...The role of the Ca^(2+)-permeable ion channel TRPC5 in regulating vasocontraction in obesity is poorly understood.Here,we investigated whether TRPC5 contributes to vascular dysfunction in obesity by promoting endothelium-dependent contraction via activation of cytosolic phospholipase A2(cPLA_(2))in the aortic endothelial cells of obese mice.Acetylcholine-induced endothelium-dependent relaxation and contraction in the aorta were measured us-ing wire myography.PLA_(2)activity was measured by the fluorogenic PLA_(2)substrate Bis-BODIPY^(TM)FL C_(11)-PC.The intracellular Ca^(2+)level in response to acetylcholine was measured by Fluo-4 fluorescence.Endothelium-derived contracting factors were assessed by enzyme immunoassay.Diet-induced obesity(DIO)attenuated endothelium-dependent vasodilation,enhanced endothelium-dependent contraction(EDC),and increased the expression of TRPC5 in the mouse aorta.Activation of TRPC5 promoted EDC in the wild-type mouse aorta,whereas pharma-cological inhibition and genetic knockout of TRPC5 decreased EDC in the DIO mouse aorta.Moreover,cPLA_(2)phosphorylation and activity were higher in aortic endothelial cells from DIO mice,and this was attenuated by inhibition and knockout of TRPC5.Cyclooxygenase 2(COX-2)expression was increased in DIO mouse endothe-lium and was decreased by a TRPC5 inhibitor and knockout of TRPC5.Release of prostaglandins F_(2α(PGF_(2α)and E 2(PGE 2)was involved in TRPC5-regulated EDC in DIO mice.This study demonstrated that TRPC5 contributes to endothelial and vascular dysfunction and is involved in EDC through activation of cPLA_(2)and enhanced COX-2-PGF_(2α)/PGE_(2)levels in DIO mice.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grants No.81622007,81960662,and 82000291)the Chang Jiang Scholars Program(Grant No.Q2015106)+3 种基金Fundamental Research Funds for the Central Universities(Grant No.JUSRP51704A)the National First-class Discipline Program of Food Science and Technology(Grant No.JUFSTR20180101)Fundamental Research Funds for Young Scholars of Jiangnan University(Grant No.JUSRP12046)the Natural Science Foundation for Young Scholars of Jiangsu Province(Grant No.BK20190596).
文摘The role of the Ca^(2+)-permeable ion channel TRPC5 in regulating vasocontraction in obesity is poorly understood.Here,we investigated whether TRPC5 contributes to vascular dysfunction in obesity by promoting endothelium-dependent contraction via activation of cytosolic phospholipase A2(cPLA_(2))in the aortic endothelial cells of obese mice.Acetylcholine-induced endothelium-dependent relaxation and contraction in the aorta were measured us-ing wire myography.PLA_(2)activity was measured by the fluorogenic PLA_(2)substrate Bis-BODIPY^(TM)FL C_(11)-PC.The intracellular Ca^(2+)level in response to acetylcholine was measured by Fluo-4 fluorescence.Endothelium-derived contracting factors were assessed by enzyme immunoassay.Diet-induced obesity(DIO)attenuated endothelium-dependent vasodilation,enhanced endothelium-dependent contraction(EDC),and increased the expression of TRPC5 in the mouse aorta.Activation of TRPC5 promoted EDC in the wild-type mouse aorta,whereas pharma-cological inhibition and genetic knockout of TRPC5 decreased EDC in the DIO mouse aorta.Moreover,cPLA_(2)phosphorylation and activity were higher in aortic endothelial cells from DIO mice,and this was attenuated by inhibition and knockout of TRPC5.Cyclooxygenase 2(COX-2)expression was increased in DIO mouse endothe-lium and was decreased by a TRPC5 inhibitor and knockout of TRPC5.Release of prostaglandins F_(2α(PGF_(2α)and E 2(PGE 2)was involved in TRPC5-regulated EDC in DIO mice.This study demonstrated that TRPC5 contributes to endothelial and vascular dysfunction and is involved in EDC through activation of cPLA_(2)and enhanced COX-2-PGF_(2α)/PGE_(2)levels in DIO mice.
