Role and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α in inhibiting aortic valve interstitial cell activation
Objective To investigate the role and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α(PGC-1α)in the activation of aortic valve interstitial cells(AVICs)in aortic stenosis.Methods Isolating primary AVICs and stimulating their activation with transforming growth factor β1(TGF-β1,30 ng/mL),the expression of PGC-1α was detected.The activation of AVICs induced by TGF-β1 was observed after overexpression of PGC-1α by adenovirus or inhibition of PGC-1α function by GW9662.The possible downstream molecular mechanism of PGC-1α in AVICs activation was screened.Finally,the phenotype was further verified in primary human AVICs.Results The expression of PGC-1α decreased after the activation of AVICs induced by TGF-β1(control group:1.00±0.18;24 h:0.31±0.10;48 h:0.32±0.06;72 h:0.20±0.07;P＜0.05).Specific overexpression of PGC-1α by adenovirus inhibited the activation of AVICs induced by TGF-β1 stimulation(periostin:3.17±0.64 vs.1.45±0.54,P＜0.05;α-smooth muscle actin:0.77±0.11 vs.0.28±0.06,P＜0.05).On the contrary,inhibition of PGC-1α function by GW9662 promoted the activation of AVICs(periostin:2.20±0.68 vs.7.99±2.50,P＜0.05).Subsequently,it was found that PGC-1αmight inhibit the activation of AVICs through downregulating the expression of calcium/calmodulin-dependent protein kinase(CAMK1δ)(0.97±0.04 vs.0.74±0.11,P＜0.05),and downregulating the expression of CAMK1δ alleviated the activation of AVICs(periostin:1.76±0.11 vs.0.99±0.20,P＜0.05).The possible mechanism was that the activation of mammalian target of rapamycin(mTOR)signaling pathway was inhibited by reducing the accumulation of reactive oxygen species(ROS)(778.3±139.4 vs.159.3±43.2,P＜0.05).Finally,the protective effect of PGC-1α overexpression was verified in the activated phenotype of human AVICs(periostin:2.73±0.53 vs.1.63±0.14,P＜0.05;connective tissue growth factor:1.27±0.04 vs.0.48±0.09,P＜0.05).Conclusions The expression of PGC-1α significantly decreases during the activation of AVICs induced by TGF-β1.The overexpression of PGC-1α significantly inhibites the activation of AVICs,suggesting that PGC-1α plays a protective role in the activation of AVICs.The possible mechanism is that PGC-1α can inhibit the activation of CAMK1δ-ROS-mTOR pathway.In conclusion,interventions based on PGC-1α expression levels are new potential therapeutic targets for aortic stenosis.
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