Dookun Emily, Walaszczyk Anna, Redgrave Rachael, Palmowski Pawel, Tual-Chalot Simon, Suwana Averina, Chapman James, Jirkovsky Eduard, Donastorg Sosa Leticia, Gill Eleanor, Yausep Oliver E, Santin Yohan, Mialet-Perez Jeanne, Andrew Owens W, Grieve David, Spyridopoulos Ioakim, Taggart Michael, Arthur Helen M, Passos João F, Richardson Gavin D
Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
School of Environmental Sciences, Faculty of Science, Agriculture & Engineering, Newcastle University, Newcastle upon Tyne, UK.
Aging Cell. 2020 Oct;19(10):e13249. doi: 10.1111/acel.13249. Epub 2020 Sep 29.
A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.
心脏缺血再灌注损伤（IRI）的一个关键组成部分是活性氧生成增加，这会导致心肌梗死患者在干预后炎症加剧和组织功能障碍。在本研究中，我们假设缺血再灌注引起的氧化应激会诱导衰老，而衰老会导致心脏IRI的病理生理过程。我们证明，IRI会在心肌细胞和间质细胞群体中诱导细胞衰老，缺血再灌注后使用衰老细胞溶解药物navitoclax进行治疗可改善左心室功能、增加心肌血管生成并减小瘢痕大小。基于SWATH-MS的蛋白质组学研究表明，缺血再灌注后增加的与纤维化和炎症相关的生物学过程在清除衰老细胞后会减弱。此外，navitoclax治疗降低了促炎、促纤维化和抗血管生成细胞因子的表达，包括γ干扰素诱导蛋白10、转化生长因子-β3、白细胞介素-11、白细胞介素-16和趋化因子。我们的研究提供了概念验证证据，证明细胞衰老会导致心脏缺血再灌注后心脏功能受损和不良重塑。我们还证实，IRI后衰老相关分泌表型（SASP）在炎症反应中起重要作用。随后，在临床可行的时间点进行衰老细胞溶解治疗可减弱该反应的多个组成部分，并改善临床重要参数。因此，细胞衰老代表了一种潜在的新型治疗途径，可改善心脏缺血再灌注患者的预后。
