Activation of the Metabolic Master Regulator PPARγ: A Potential PlOneering Therapy for Pulmonary Arterial Hypertension
Activation of the Metabolic Master Regulator PPARγ: A Potential PlOneering Therapy for Pulmonary Arterial Hypertension
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DOI：
10.1165/rcmb.2019-0226ps
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发表时间：
2020-02-01
影响因子：
6.4
通讯作者：
Chan, Stephen Y.
中科院分区：
文献类型：
--
作者：
Hansmann, Georg;Calvier, Laurent;Chan, Stephen Y.
转化研究对于通过使用类似于人类肺动脉高压（PAH）、心血管重构和进行性右心衰竭的动物模型的体内机制研究开发用于治疗肺血管疾病、肺动脉高压和心力衰竭的反向重构策略至关重要。自2007年以来，过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂已成为治疗PAH的有前景的新型、抗增殖、抗胰岛素、胰岛素增敏、有效药物。然而，早期糖尿病研究结果，其随后的误解，发表的综述文章中的错误，以及文献中关于潜在不良反应的谣言，都抑制了考虑药物PPAR-gamma激活治疗心血管疾病（包括PAH）的热情。最近，噻唑烷二酮类PPAR γ激动剂吡格列酮经历了临床复兴，特别是基于IRIS（卒中后胰岛素抵抗干预）研究，这是一项在3，876例短暂性脑缺血发作/缺血性卒中后无糖尿病状态的患者中进行的随机对照试验，临床随访4.8年。我们讨论了临床前的基本翻译结果和随机对照试验的有益和不良反应的噻唑烷二酮类的PPAR-gamma激动剂，特别是在过去5年的重点。其目标是采用数据驱动的方法，直接建立临床前和临床研究记录。最近关于在高风险人群中缺乏显著毒性的令人信服的临床试验数据证明及时进行临床研究以实现吡格列酮治疗临床PAH的“再利用”或“重新定位”是合理的。
Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPAR-gamma activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPAR gamma agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPAR-gamma agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.