Smooth Muscle Overexpression of PGC1 alpha Attenuates Atherosclerosis in Rabbits
Smooth Muscle Overexpression of PGC1 alpha Attenuates Atherosclerosis in Rabbits
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PGC1 α 平滑肌过度表达可减轻兔的动脉粥样硬化
DOI：
10.1161/circresaha.120.317705
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发表时间：
2021
影响因子：
20.1
通讯作者：
Jiang Xiaohong
中科院分区：
文献类型：
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作者：
Wei Zhe;Chong Hoshun;Jiang Qixia;Tang Yuhang;Xu Jinhong;Wang Haoquan;Shi Yanteng;Cui Le;Li Jing;Zhang Yujing;Xue Yunxing;Li Jutang;Liu George;Chen Xi;Wang Dongjin;Zhang Chen-Yu;Jiang Xiaohong
靶向血管平滑肌细胞（VSMC）表型转换是一种有前途的动脉粥样硬化治疗方法。PGC 1 α调节异常（过氧化物酶体增殖物激活受体γ，共激活因子1α）是细胞能量代谢的关键调节因子，与动脉粥样硬化的发病机制有关，目前的研究旨在确定VSMCs中的PGC 1 α是否以及如何调节动脉粥样硬化的进展。方法和结果我们用SMC-特异性PGC 1 α过表达，并显示这些兔子在高胆固醇饮食喂养后比其非转基因同窝仔发生主动脉粥样硬化明显较少，而总血浆胆固醇水平相似。正如VSMC分化标志物基因的恢复表达所示，高胆固醇饮食诱导的主动脉中膜表型转换在转基因兔中基本上被逆转，伴随着合成表型基因、促炎细胞因子、粘附分子、巨噬细胞浸润、基质金属蛋白酶（MMP）、活性氧产生和衰老水平的降低。离体研究进一步表明，VSMC特异性PGC 1 α过表达显著抑制了高胆固醇饮食喂养对SRF（血清反应因子）与ELK 1（ETS转录因子ELK 1）（一种TCF（三元复合因子），在VSMC中作为肌源性阻遏物）相关的促进作用，从而保留了VSMC收缩表型。此外，PGC 1 α基因敲低可显著增加ERK（extracellular signal-regulated kinase，细胞外信号调节激酶）1/2-ELK-1信号通路，促进VSMCs表型转换和增殖。此外，我们发现PGC 1 α可以通过调节过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPAR γ）的活性来调节表皮生长因子受体（epidermal growth factor receptor，EGFR）-丝裂原活化蛋白激酶（mitogen-activated protein kinase，ERK）信号通路。最后，我们发现，这些有益的结果SMC特异性PGC 1 α过表达可以外推从兔到人VSMCs和clinical settings.ConclusionsWe证明了一个关键的作用，PGC 1 α在维持VSMCs的收缩表型，并强调了治疗动脉粥样硬化的PGC 1 α的潜力。
RationaleTargeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis. Dysregulation of PGC1α (peroxisome proliferator-activated receptor gamma, coactivator 1α), a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of atherosclerosis, yet its role in atherosclerosis remains controversial.ObjectiveThe current study aimed to determine whether and how PGC1α in VSMCs regulates atherosclerosis progression.Methods and ResultsWe generated transgenic rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic atherosclerosis than their nontransgenic littermates after high-cholesterol diet feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the high-cholesterol diet-induced phenotypic switching in the aortic media was largely reversed in transgenic rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, MMPs (matrix metalloproteinases), reactive oxygen species production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of high-cholesterol diet feeding on the association of SRF (serum response factor) with ELK1 (ETS transcription factor ELK1), a TCF (ternary complex factor) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased ERK (extracellular signal-regulated kinase)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR (epidermal growth factor receptor)-ERK1/2 MAPK (mitogen-activated protein kinase) signaling via modulating PPARγ (peroxisome proliferator-activated receptor γ) activity in RVSMCs (rabbit vascular smooth muscle cells). Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings.ConclusionsWe demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for atherosclerosis.