Mutual inhibitory mechanisms between PPARγ and Hif-1α: implication in pulmonary hypertension.
Mutual inhibitory mechanisms between PPARγ and Hif-1α: implication in pulmonary hypertension.
复制标题
DOI：
10.14800/rci.626
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang K;Jiang Q;Wang Z;Li M;Zhang Q;Lu W;Wang J
转录因子缺氧诱导因子1α(HIF-1α)在肺动脉高压(PH)的发病机制中起重要作用。以往的研究表明，HIF-1α通过触发细胞内钙稳态，尤其是钙内流过程，增加远端肺动脉压力和血管重塑的深层机制。在我们最近发表在《分子医学杂志》上的研究论文中，我们发现转录因子过氧化物酶体增殖物激活受体γ(PPARγ)的激活可以通过抑制PA远端压力升高和血管重构来减轻PH的发病。此外，这些作用可能是通过抑制HIF-1α来抑制SOCE而实现的。这些结果为PPARγ在PH治疗中的保护作用提供了令人信服的证据和新的机制。然后，通过综合功能丧失和功能获得策略，我们进一步确定了PPARγ和HIF-1α之间存在相互抑制机制。基本上，在慢性低氧应激下，Hif-1α积聚导致PPARγ表达缺失，PPARγ和Hif-1α逐渐失衡，促进了PH的进展；而靶向PPARγ修复途径反向抑制了Hif-1α水平和Hif-1α介导的信号转导，从而减轻了PH发病机制下的肺动脉压升高和血管重构。
Transcription factor hypoxia-inducible factor 1α (Hif-1α) is known for its crucial role in promoting the pathogenesis of pulmonary hypertension (PH). Previous studies have indicated the in-depth mechanisms that Hif-1α increases the distal pulmonary arterial (PA) pressure and vascular remodeling by triggering the intracellular calcium homeostasis, especially the store-operated calcium entry (SOCE) process. In our recent research paper published in the Journal of Molecular Medicine, we found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) activation could attenuate the PH pathogenesis by suppressing the elevated distal PA pressure and vascular remodeling. Moreover, these effects are likely mediated through the inhibition of SOCE by suppressing Hif-1α. These results provided convincing evidence and novel mechanisms in supporting the protective roles of PPARγ on PH treatment. Then, by using comprehensive loss-of-function and gain-of-function strategies, we further identified the presence of a mutual inhibitory mechanism between PPARγ and Hif-1α. Basically, under chronic hypoxic stress, accumulated Hif-1α leads to abolished expression of PPARγ and progressive imbalance between PPARγ and Hif-1α, which promotes the PH progression; however, targeted PPARγ restoration approach reversely inhibits Hif-1α level and Hif-1α mediated signaling transduction, which subsequently attenuates the elevated pulmonary arterial pressure and vascular remodeling under PH pathogenesis.