Abstract
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.
Highlights
The number of patients with diabetes mellitus (DM) has been increasing at an alarming rate for decades (Guariguata et al, 2014; Wang H et al, 2019)
The results showed that left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly lower in the DM group compared with the control group, while the impairment of cardiac function was reduced in the DM + Ran group compared with the DM group (Figures 1F,G)
We elucidated for the first time the involvement of miR-135b inhibition of pyroptosis in the treatment of diabetic cardiac fibrosis with ranolazine (Figure 6)
Summary
The number of patients with diabetes mellitus (DM) has been increasing at an alarming rate for decades (Guariguata et al, 2014; Wang H et al, 2019). Cardiac fibrosis is the main pathological feature of DCM and can increase the risk of heart failure, arrhythmia and sudden death (Asbun and Villarreal, 2006). Cardiac fibrosis is often accompanied by increase in the levels of inflammatory factors (Palomer et al, 2020). Recent studies have revealed that gasdermin D (GSDMD) plays an important indicator role in pyroptosis, and the N-terminus of GSDMD creates small pores in the cell membrane, causing the release of contents and the massive entry of external substances such as water molecules, eventually lead to cell death (Kovacs and Miao, 2017). Activation of inflammatory factors and the release of cytokines, which promotes the formation of collagen deposits and fibrosis, exacerbate DCM (Bracey et al, 2014). Suppression of pyroptosis is essential for the prevention and treatment of diabetic cardiac fibrosis
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