A Novel Combination of Exogenous Klotho Combined With Telmisartan Ameliorated Diabetic Cardiomyopathy via an Antifibrotic Mechanism.

IF 3.1 3区 生物学 Q3 CELL BIOLOGY
Mansi Vinodkumar Trivedi, Hemant R Jadhav, Anil Bhanudas Gaikwad
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引用次数: 0

Abstract

Diabetic cardiomyopathy (DCM) is a progressive heart disorder associated with diabetes mellitus, leading to structural and functional cardiac abnormalities. The mechanisms responsible include renin-angiotensin-aldosterone (RAAS) activation, inflammation, apoptosis, and metabolic disturbances. Despite well-established epidemiological links, treatments for DCM are elusive. This study evaluated the efficacy of a novel combination of recombinant Klotho (KL) and the angiotensin receptor blocker telmisartan (TEL) in treating DCM, as well as investigating potential mechanisms involved. DCM was induced with a single dose of streptozotocin (55 mg/kg, i.p.), followed by a 4-week induction period. For treatment, rats were assigned to five groups: Normal control (NC), Diabetic control (DC), DC + KL (0.01 mg/kg, S.C.), DC + TEL (10 mg/kg, p.o.), and KL + TEL combination. Plasma biochemistry assessed cardiac damage (LDH, CK-MB) and stress markers (ANP, BNP). Electrocardiogram (ECG) measured heart parameters, including heart rate (HR), QTc, JT interval, RR interval, and Tpeak-Tend intervals. Histological analysis (H&E, Masson's trichrome, and Picrosirius red) was performed to assess myocardial structure and fibrosis. Lastly, immunohistochemistry analysis was performed to check the expression of transforming growth factor-β1 (TGF-β1), pSMAD 2/3, matrix metalloproteinase 9 (MMP9), and PRKN. KL and TEL combination treatment significantly reduced cardiac damage markers, reduced ECG abnormalities, including QTc, improved HR while suppressing pro-fibrotic signaling, enhancing mitophagy, and decreasing fibroblast proliferation. The involvement of pathways involving TGF-β1, pSMAD-2/3, MMP9, and pFOXO3a conferred protection to the heart in experimental in-vivo settings. These findings suggest that the combination of KL and TEL effectively mitigates key pathological features of DCM, highlighting its potential as a targeted treatment strategy.

外源性克罗索联合替米沙坦通过抗纤维化机制改善糖尿病性心肌病。
糖尿病性心肌病(DCM)是一种与糖尿病相关的进行性心脏疾病,可导致心脏结构和功能异常。其机制包括肾素-血管紧张素-醛固酮(RAAS)激活、炎症、细胞凋亡和代谢紊乱。尽管建立了流行病学联系,但DCM的治疗方法仍难以捉摸。本研究评估了重组Klotho (KL)和血管紧张素受体阻滞剂替米沙坦(TEL)联合治疗DCM的疗效,并探讨了可能的机制。采用单剂量链脲佐菌素(55 mg/kg, ig)诱导大鼠DCM,诱导期4周。将大鼠分为5组:正常对照组(NC)、糖尿病对照组(DC)、DC + KL (0.01 mg/kg, S.C.)、DC + TEL (10 mg/kg, p.o.)和KL + TEL联合组。血浆生化评估心脏损伤(LDH, CK-MB)和应激标志物(ANP, BNP)。心电图(ECG)测量心脏参数,包括心率(HR)、QTc、JT间期、RR间期、Tpeak-Tend间期。组织学分析(H&E、马松三色和小天狼星红)评估心肌结构和纤维化。最后通过免疫组化检测转化生长因子-β1 (TGF-β1)、pSMAD 2/3、基质金属蛋白酶9 (MMP9)、PRKN的表达。KL和TEL联合治疗可显著降低心脏损伤标志物,降低ECG异常,包括QTc,改善HR,同时抑制促纤维化信号,增强线粒体自噬,降低成纤维细胞增殖。TGF-β1、pSMAD-2/3、MMP9和pFOXO3a通路的参与在实验体内环境中赋予心脏保护作用。这些发现表明,KL和TEL联合治疗可有效缓解DCM的关键病理特征,突出了其作为靶向治疗策略的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
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