Enhancing PPARγ by HDAC inhibition reduces foam cell formation and atherosclerosis in ApoE deficient mice
Enhancing PPARγ by HDAC inhibition reduces foam cell formation and atherosclerosis in ApoE deficient mice
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通过 HDAC 抑制增强 PPARγ 可减少 ApoE 缺陷小鼠的泡沫细胞形成和动脉粥样硬化
DOI：
10.1016/j.phrs.2020.105059
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发表时间：
2020-10-01
影响因子：
9.3
通讯作者：
Cao, Wangsen
中科院分区：
文献类型：
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作者：
Gao, Qi;Wei, Ai;Cao, Wangsen
动脉粥样硬化（AS）是一种危险的心血管疾病，治疗选择有限。据报道，各种泛或类型选择性组蛋白脱乙酰酶（HDAC）抑制剂对动脉粥样硬化（AS）具有动脉粥样硬化保护作用;然而，介导保护作用的关键效应物和主要细胞过程仍不清楚。在这里，我们报告说，过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ），一个转录因子，积极参与脂质代谢，具有强大的组织保护和抗炎特性，是一个关键的调解人的抗动脉粥样硬化作用的HDAC抑制。我们发现，一种众所周知的泛HDAC抑制剂TSA（曲古抑菌素A）减少了巨噬细胞的泡沫细胞形成，伴随着PPAR γ及其下游胆固醇外排转运蛋白ABCA 1（ATP结合膜盒转运蛋白A1）和ABCG 1的显著升高。在高脂饮食喂养的ApoE（-/-）小鼠的AS模型中，TSA治疗减轻了AS病变，类似地增加了PPAR γ和下游胆固醇转运蛋白，并减轻了炎症细胞因子TNF α和IL-1 β的诱导。探索PPAR γ升高的潜在原因显示TSA诱导C/EBP α（CCAAT增强子结合蛋白α）（PPAR γ的上游调节因子）的乙酰化，通过该乙酰化增加PPAR γ的反式激活。更重要的是，我们产生了一个株的PPAR γ/ApoE双敲除小鼠，并证明，缺乏PPAR γ废除TSA对腹腔巨噬细胞的泡沫细胞形成和AS发病机制的保护作用。综上所述，这些结果揭示了C/EBP α和PPAR γ是介导泡沫细胞形成和AS发展的表观遗传信号通路的HDAC敏感组分，并表明通过HDAC抑制剂靶向C/EBP α/PPAR γ轴具有延缓AS和相关心血管疾病进展的治疗潜力。
Atherosclerosis (AS) is a risky cardiovascular disease with limited treatment options. Various pan or type-selective histone deacetylase (HDAC) inhibitors are reportedly atheroprotective against atherosclerosis (AS); however, the key effectors and the main cellular processes that mediate the protective effects remain poorly defined. Here, we report that PPAR gamma (Peroxisome proliferator-activated receptor gamma), a transcription factor actively involved in lipid metabolism with strong tissue protective and anti-inflammation properties, is a critical mediator of the anti-AS effects by HDAC inhibition. We showed that a well-known pan-HDAC inhibitor TSA (Trichostatin A) reduced foam cell formation of macrophages that is accompanied by a marked elevation of PPAR gamma and its downstream cholesterol efflux transporter ABCA1 (ATP-binding membrane cassette transport protein A1) and ABCG1. In an AS model of ApoE(-/-) mice fed on high-fat diet, TSA treatment alleviated AS lesions, similarly increased PPAR gamma and the downstream cholesterol transporters and mitigated the induction of inflammatory cytokine TNF alpha and IL-1 beta. Exploring the potential cause of PPAR gamma elevation revealed that TSA induced the acetylation of C/EBP alpha (CCAAT enhancer binding protein alpha), the upstream regulator of PPAR gamma, through which it increased PPAR gamma transactivation. More importantly, we generated a strain of PPAR gamma/ApoE double knockout mice and demonstrated that lack of PPAR gamma abrogated the protective effects of TSA on foam cell formation of peritoneal macrophages and the AS pathogenesis. Taken together, these results unravel that C/EBP alpha and PPAR gamma are the HDAC-sensitive components of an epigenetic signaling pathway mediating foam cell formation and AS development, and suggest that targeting C/EBP alpha/PPAR gamma axis by HDAC inhibitors possesses therapeutic potentials in retarding the progression of AS and the related cardiovascular diseases.