Ren Long, Chen Xi, Nie Binyang, Qu Huan, Ju Jiaming, Bai Yunlong
Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Front Mol Biosci. 2022 Jan 26;9:806966. doi: 10.3389/fmolb.2022.806966. eCollection 2022.
Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus (DM), and cardiac fibrosis is a characteristic pathological manifestation of DCM. DCM can be exacerbated by pyroptosis, and pyroptosis is a potential target of microRNAs (miRNAs). miR-135b is involved in delaying the progression of numerous cardiovascular diseases, Nonetheless, the role of miR-135b in diabetic cardiac fibrosis is unclear. Ranolazine is a piperazine derivative and is effective for the treatment of cardiovascular disease. The purpose of the study was to elucidate the mechanism of action of ranolazine against diabetic cardiac fibrosis and to investigate the role of miR-135b in this process. Functional and structural changes in the rat heart were examined by echocardiography, hematoxylin-eosin (H&E) and Masson staining. Immunohistochemistry was used to assess the expression of caspase-1, interleukin-1β (IL-1β), gasdermin D (GSDMD), transforming growth factor-β1 (TGF-β1), collagen I and collagen III in the rat left ventricle. Western blot and immunofluorescence were used to detect the protein expression of caspase-1, IL-1β, GSDMD, TGF-β1, collagen I and collagen III proteins, and the mRNA levels were determined using fluorescent quantitative PCR. Ranolazine reduced pyroptosis and inhibited collagen deposition, improving cardiac function in rats. Ranolazine increased miR-135b expression in high glucose-treated cardiac fibroblasts, and miR-135b directly bound to caspase-1. Interference with miR-135b reduced the effects of ranolazine on pyroptosis and collagen deposition. Ranolazine treatment of diabetic cardiac fibrosis inhibited pyroptosis and collagen deposition by upregulating miR-135b. Our study provides a solid theoretical basis for understanding the pathogenesis of diabetic cardiac fibrosis and the clinical use of ranolazine in the treatment of DCM.
糖尿病性心肌病（DCM）是糖尿病（DM）的一种主要心血管并发症，而心脏纤维化是DCM的特征性病理表现。DCM可因细胞焦亡而加重，且细胞焦亡是微小RNA（miRNA）的一个潜在靶点。miR-135b参与延缓多种心血管疾病的进展，然而，miR-135b在糖尿病性心脏纤维化中的作用尚不清楚。雷诺嗪是一种哌嗪衍生物，对心血管疾病的治疗有效。本研究旨在阐明雷诺嗪抗糖尿病性心脏纤维化的作用机制，并探讨miR-135b在此过程中的作用。通过超声心动图、苏木精-伊红（H&E）染色和Masson染色检查大鼠心脏的功能和结构变化。采用免疫组织化学法评估大鼠左心室中半胱天冬酶-1、白细胞介素-1β（IL-1β）、gasdermin D（GSDMD）、转化生长因子-β1（TGF-β1）、Ⅰ型胶原和Ⅲ型胶原的表达。采用蛋白质印迹法和免疫荧光法检测半胱天冬酶-1、IL-1β、GSDMD、TGF-β1、Ⅰ型胶原和Ⅲ型胶原蛋白的表达，并使用荧光定量PCR测定mRNA水平。雷诺嗪减少细胞焦亡并抑制胶原沉积，改善大鼠心脏功能。雷诺嗪增加高糖处理的心脏成纤维细胞中miR-135b的表达，且miR-135b直接与半胱天冬酶-1结合。干扰miR-135b可降低雷诺嗪对细胞焦亡和胶原沉积的影响。雷诺嗪治疗糖尿病性心脏纤维化通过上调miR-135b抑制细胞焦亡和胶原沉积。我们的研究为理解糖尿病性心脏纤维化的发病机制以及雷诺嗪在DCM治疗中的临床应用提供了坚实的理论基础。
