【摘 要】
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Vascular calcification(VC)is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process,in which vascular smooth muscle cells(VSMCs)transform into osteoblast/chondrocyte-like cells as
【机 构】
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Minhang Hospital&Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 201203,Chin
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Vascular calcification(VC)is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process,in which vascular smooth muscle cells(VSMCs)transform into osteoblast/chondrocyte-like cells as in bone formation.VC is associated with significant morbidity and mortality in chronic kidney disease(CKD)and cardiovascular disease,but the underlying mechanisms remain unclear.In this study we investigated the role of large-conductance calcium-activated potassium(BK)channels in 3 experimental VC models.VC was induced in vascular smooth muscle cells(VSMCs)by β-glycerophosphate(β-GP),or in rats by subtotal nephrectomy,or in mice by high-dosage vitamin D3.We showed that the expression of BK channels in the artery of CKD rats with VC and in β-GP-treated VSMCs was significantly decreased,which was functionally confirmed by patch-clamp recording.In β-GP-treated VSMCs,BK channel opener NS1619(20 μM)significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity.Furthermore,NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN,as well as Runx2(a key transcription factor involved in preosteoblast to osteoblast differentiation),and increased the expression of α-SMA protein,whereas BK channel inhibitor paxilline(10 μM)caused the opposite effects.In primary cultured VSMCs from BK-/-mice,BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs.Moreover,calcification was more severe in thoracic aorta rings of BK-/-mice than in those of wild-type littermates.Administration of BK channel activator BMS191011(10 mg·kg-1·d-1)in high-dosage vitamin D3-treated mice significantly ameliorated calcification.Finally,co-treatment with Akt inhibitor MK2206(1 μM)or FoxO1 inhibitor AS1842856(3 μM)in calcified VSMCs abrogated the effects of BK channel opener NS1619.Taken together,activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways.Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.
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