Di Lisa Fabio, Bernardi Paolo
Dipartimento di Scienze Biomediche, Via Ugo Bassi 58/B, I-35121 Padova, Italy.
Curr Med Chem. 2015;22(20):2480-7. doi: 10.2174/0929867322666150530210005.
In the last twenty years, numerous reports provided solid evidence on the involvement of the mitochondrial permeability transition pore (PTP) in myocardial injury caused by ischemia and reperfusion. Indeed, significant cardioprotection is obtained by reducing the open probability of the PTP. This goal has been achieved by pharmacological and genetic interventions aimed at inhibiting cyclophilin D (CyPD), a regulatory protein that favors PTP opening. On the other hand, CyPD inhibition or deletion has been shown to worsen remodeling of the hypertrophic heart, an adverse outcome that must find an explanation within PTP modulation by CyPD. In this review, recent advancements in defining the molecular identity of the PTP are analyzed in relation to its pathophysiological functions and pharmacological modulation. In this respect, advantages and limitations of compounds targeting CyPD are discussed with the analysis of novel PTP inhibitors that do not interact with CyPD.
在过去二十年中，大量报告提供了确凿证据，证明线粒体通透性转换孔（PTP）参与了缺血再灌注引起的心肌损伤。事实上，通过降低PTP的开放概率可获得显著的心脏保护作用。这一目标已通过旨在抑制亲环蛋白D（CyPD）的药理学和遗传学干预得以实现，CyPD是一种促进PTP开放的调节蛋白。另一方面，CyPD抑制或缺失已被证明会使肥厚性心脏的重塑恶化，这一不良结果必须在CyPD对PTP的调节中找到解释。在本综述中，结合PTP的病理生理功能及其药理学调节，分析了在确定PTP分子身份方面的最新进展。在这方面，通过分析不与CyPD相互作用的新型PTP抑制剂，讨论了靶向CyPD的化合物的优缺点。
