PDF(Pubmed)
Abstract：
The long-term high-fat diet (HFD) can cause myocardial lipotoxicity, which is characterized pathologically by myocardial hypertrophy, fibrosis, and remodeling and clinically by cardiac dysfunction and heart failure in patients with obesity and diabetes. Circular RNAs (circRNAs), a novel class of noncoding RNA characterized by a ring formation through covalent bonds, play a critical role in various cardiovascular diseases. However, few studies have been conducted to investigate the role and mechanism of circRNA in myocardial lipotoxicity. Here, we found that circ_005077, formed by exon 2-4 of Crmp1, was significantly upregulated in the myocardium of an HFD-fed rat. Furthermore, we identified circ_005077 as a novel ferroptosis-related regulator that plays a role in palmitic acid (PA) and HFD-induced myocardial lipotoxicity in vitro and in vivo. Mechanically, circ_005077 interacted with Cyclophilin A (CyPA) and inhibited its degradation via the ubiquitination proteasome system (UBS), thus promoting the interaction between CyPA and p47phox to enhance the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase responsible for ROS generation, subsequently inducing ferroptosis. Therefore, our results provide new insights into the mechanisms of myocardial lipotoxicity, potentially leading to the identification of a novel therapeutic target for the treatment of myocardial lipotoxicity in the future.
摘要：
长期高脂饮食(HFD)可引起心肌脂毒性,其病理特征是心肌肥大，纤维化，肥胖和糖尿病患者的心功能不全和心力衰竭的临床重塑。环状RNA（circularRNAs），一类新的非编码RNA，其特征是通过共价键形成环，在各种心血管疾病中起关键作用。然而,很少有研究探讨circRNA在心肌脂毒性中的作用和机制。这里,我们发现由Crmp1的外显子2-4形成的circ_005077在HFD喂养的大鼠的心肌中显著上调。此外，我们确定circ_005077是一种新型的铁凋亡相关调节因子，在体内和体外对棕榈酸（PA）和HFD诱导的心肌脂毒性起作用。机械上,circ_005077与亲环蛋白A（CyPA）相互作用，并通过泛素化蛋白酶体系统（UBS）抑制其降解，从而促进CyPA和p47phox之间的相互作用，以增强负责ROS产生的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的活性，随后诱导铁性凋亡。因此,我们的结果为心肌脂毒性的机制提供了新的见解，有可能导致未来确定一种新的治疗心肌脂毒性的治疗靶点。
