Downregulated expression of cold-inducible RNA binding protein (CIRP), a stress-response protein, has been demonstrated in the hearts of patients with heart failure (HF). However, whether CIRP plays a critical role in the pathogenesis of HF remains unknown. Zr17-2 is a recently identified CIRP agonist, which can enhance the expression of CIRP in hearts. Herein, we evaluated the effects of zr17-2 on the development of HF in a rat model of myocardial infarction (MI). Male SD rats were pretreated with CIRP agonist zr17-2 or vehicle saline for 6 consecutive days, followed by MI induction. 1-week post-MI, cardiac function, and structural and molecular changes were determined by echocardiography and molecular biology methods. Excitingly, we found that pretreatment with zr17-2 significantly attenuated MI-induced cardiac dysfunction and dilation, coupled with reduced infarction size and cardiac remodeling. In addition, increased inflammatory response in the peri-infarcted heart including macrophage infiltration and the expression of inflammatory genes were all significantly decreased by zr17-2 pretreatment, suggesting an anti-inflammatory effect of zr17-2. Moreover, zr17-2 pretreatment also upregulated the antioxidant genes (e.g. NQO-1, Nrf2, and HO-1) level in the hearts. In isolated cultured cardiomyocytes, pretreatment with zr17-2 markedly attenuated cell injury and apoptosis induced by oxidative injury, along with elevation of Nrf2-related antioxidant genes and CIRP. However, silencing CIRP abolished zr17-2’s antioxidant effects against oxidative injury, confirming that zr17-2’s role is dependent on CIRP. Collectively, our study suggests CIRP plays a crucial role in the development of HF and a beneficial effect of CIRP agonist in preventing MI-induced HF, possibly via anti-inflammatory and anti-oxidant pathways.

中文翻译：

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CIRP 激动剂上调可预防心肌梗死大鼠心力衰竭的发生

冷诱导 RNA 结合蛋白 (CIRP)（一种应激反应蛋白）的表达下调，已在心力衰竭 (HF) 患者的心脏中得到证实。然而，CIRP 是否在心力衰竭的发病机制中发挥关键作用仍不清楚。 Zr17-2是最近发现的CIRP激动剂，可以增强心脏中CIRP的表达。在此，我们评估了 zr17-2 对大鼠心肌梗死 (MI) 模型中心力衰竭发展的影响。雄性SD大鼠用CIRP激动剂zr17-2或载体生理盐水预处理连续6天，然后进行MI诱导。 MI后1周，通过超声心动图和分子生物学方法测定心功能以及结构和分子变化。令人兴奋的是，我们发现 zr17-2 预处理可显着减轻 MI 引起的心脏功能障碍和扩张，同时减少梗死面积和心脏重塑。此外，zr17-2预处理后梗死周围心脏中增加的炎症反应（包括巨噬细胞浸润）和炎症基因的表达均显着降低，表明zr17-2具有抗炎作用。此外，zr17-2预处理还上调了心脏中的抗氧化基因（例如NQO-1、Nrf2和HO-1）水平。在分离培养的心肌细胞中，用 zr17-2 预处理可显着减轻氧化损伤诱导的细胞损伤和细胞凋亡，同时提高 Nrf2 相关抗氧化基因和 CIRP。然而，沉默CIRP会消除zr17-2针对氧化损伤的抗氧化作用，证实zr17-2的作用依赖于CIRP。总的来说，我们的研究表明 CIRP 在心力衰竭的发生中起着至关重要的作用，并且 CIRP 激动剂可能通过抗炎和抗氧化途径在预防 MI 诱发的心力衰竭方面发挥有益作用。