Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People's Republic of China.
Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, China.
J Transl Med. 2024 Mar 22;22(1):297. doi: 10.1186/s12967-024-05098-7.
The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear.
RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson's analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM.
The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.
I 型胶原（Col1）的异常分泌和过度沉积是扩张型心肌病（DCM）心肌纤维化发病机制中的重要因素。然而，Col1 合成和分泌的确切分子机制尚不清楚。
RNA 测序分析显示，DCM 患者的 HtrA 丝氨酸肽酶 1（HTRA1）表达增加，与心肌纤维化强烈相关。免疫印迹、定量逆转录聚合酶链反应（qRT-PCR）、免疫组织化学和免疫荧光分析在人和小鼠组织中均得到一致的发现。Pearson 分析显示，HTRA1 水平与 DCM 患者的心肌纤维化指标（包括细胞外容积分数（ECV）、固有 T1 和晚期钆增强（LGE））之间存在显著正相关。体外实验表明，抑制 HTRA1 可抑制心脏成纤维细胞向肌成纤维细胞的转化，并减少 Col1 的分泌。进一步的研究确定了 HTRA1 在促进内质网（ER）出口位点形成中的作用，这促进了 Col1 从 ER 到高尔基体的运输，从而增加其分泌。相反，HTRA1 敲低会阻碍 Col1 在 ER 中的保留，引发 ER 应激，并随后诱导 ER 自噬以降解错误折叠的 Col1 并维持 ER 内稳态。使用腺相关病毒-9-shHTRA1-绿色荧光蛋白（AAV9-shHTRA1-GFP）的体内实验表明，HTRA1 敲低可有效抑制 DCM 小鼠的心肌纤维化并改善左心室功能。
本研究的结果为治疗 DCM 相关心肌纤维化提供了有价值的见解，并强调了靶向 HTRA1 介导的胶原分泌的治疗潜力。
