San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, 92182, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2019 Jan 14;10(1):187. doi: 10.1038/s41467-018-08129-2.
Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
药物激活应激响应信号通路为改善与多种疾病相关的蛋白质平衡失调提供了一种有前途的方法。然而，这种方法尚未在体内应用。在这里，我们使用心肌缺血/再灌注的小鼠模型表明，在再灌注期间（心肌梗死的典型临床干预点）选择性地激活未折叠蛋白反应 (UPR) 的 ATF6 分支，可在转录水平重新编程蛋白质稳态，减轻损伤并保护心脏功能。在心脏中特异性敲除心肌细胞中的 Atf6 后，这些作用消失，表明 ATF6 在介导药物激活的基于蛋白质稳态的心脏保护中发挥关键作用。ATF6 的药物激活在肾和脑缺血/再灌注模型中也具有保护作用，证明其具有广泛的适用性。因此，ATF6 的药物激活代表了一种基于蛋白质稳态的治疗策略，可改善缺血/再灌注损伤，突出了其在治疗由蛋白质稳态失衡引起的广泛病理的独特转化潜力。
