Qin Youfa, Ye Xiaomei, Luo Ye, Peng Luting, Zhou Guanghui, Zhu Yongkun, Pan Chunyu
Affiliated Dongguan Shilong People's Hospital of Southern Medical University, SSL Central Hospital of Dongguan City, Department of Clinical Pharmacy, Dongguan, Guangdong, China.
Southern Medical University, School of Pharmaceutical Sciences, Guangzhou, Guangdong, China.
J Appl Biomed. 2023 Apr;21(1):15-22. doi: 10.32725/jab.2023.005. Epub 2023 Apr 3.
Myocardial fibrosis is the most serious complication of viral myocarditis (VMC). This study aimed to investigate the therapeutic benefits and underlying mechanisms of lentivirus-mediated human tissue kallikrein gene transfer in myocardial fibrosis in VMC mice. We established VMC mouse model via intraperitoneal injection with Coxsackie B3 virus. The effect was then assessed after treatment with vehicle, the empty lentiviral vectors (EZ.null), and the vectors expressing hKLK1 (EZ.hKLK1) via tail vein injection for 30 days, respectively. The results showed that administering EZ.hKLK1 successfully induced hKLK1 overexpression in mouse heart. Compared with EZ.null treatment, EZ.hKLK1 administration significantly reduced the heart/weight ratio, improved cardiac function, and ameliorated myocardial inflammation in VMC mice, suggesting that hKLK1 overexpression alleviates VMC in mice. EZ.hKLK1 administration also significantly abrogated the increased myocardial collagen content, type I/III collagen ratio, TGF-β1 mRNA and protein expression in VMC mice, suggesting that hKLK1 overexpression reduces collagen accumulation and blunts TGF-β1 signaling in the hearts of VMC mice. In conclusion, our results suggest that hKLK1 alleviates myocardial fibrosis in VMC mice, possibly by downregulating TGF-β1 expression.
心肌纤维化是病毒性心肌炎（VMC）最严重的并发症。本研究旨在探讨慢病毒介导的人组织激肽释放酶基因转移对VMC小鼠心肌纤维化的治疗作用及其潜在机制。我们通过腹腔注射柯萨奇B3病毒建立VMC小鼠模型。然后分别经尾静脉注射赋形剂、空慢病毒载体（EZ.null）和表达hKLK1的载体（EZ.hKLK1）30天，之后评估其效果。结果显示，给予EZ.hKLK1成功诱导了小鼠心脏中hKLK1的过表达。与EZ.null治疗相比，给予EZ.hKLK1显著降低了VMC小鼠的心脏/体重比，改善了心脏功能，并减轻了心肌炎症，提示hKLK1过表达可减轻小鼠的VMC。给予EZ.hKLK1还显著消除了VMC小鼠心肌胶原含量、I/III型胶原比例、TGF-β1 mRNA和蛋白表达的增加，提示hKLK1过表达减少了VMC小鼠心脏中的胶原积累并减弱了TGF-β1信号传导。总之，我们的结果提示hKLK1可能通过下调TGF-β1表达来减轻VMC小鼠的心肌纤维化。
