Abstract
Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-β1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.
Highlights
Diabetes mellitus is a leading cause of cardiovascular diseases which influence the myocardium in several aspects
Cardiac fibroblasts treated for 24 h with a high-glucose medium exhibited a significant increase in cell proliferation and collagen synthesis, assessed using by quantifying 5Bromo-2′-deoxyuridine (BrdU) and 3H-proline incorporation
Pretreatment of cardiac fibroblasts with cafestol (30 or 100 μM) for 12 h followed by exposure to high levels of glucose resulted in significant reductions in high-glucose-increased cell proliferation and collagen synthesis as determined by BrdU incorporation and 3H-proline incorporation (Figures 1(a) and 1(b), respectively)
Summary
Diabetes mellitus is a leading cause of cardiovascular diseases which influence the myocardium in several aspects. A number of mediators are involved in this process, the most important is hyperglycemia which causes glycation of proteins and triggers reactive oxygen species (ROS) production [1]. Increasing evidence has demonstrated that transforming growth factor-β1 (TGF-β1), a prosclerotic cytokine, is involved in cardiac fibrosis and that its expression is increased in patients with diabetes [2]. Evidence-Based Complementary and Alternative Medicine high-glucose concentrations (or hyperglycemia) have been demonstrated to stimulate cardiac fibroblast proliferation, increase fibroblast collagen production, and mediate increases in TGF-β1 activity and downstream canonical Smad signaling [3]. Ese studies have indicated that oxidative stress plays a critical role in the diabetic induction of myocardial fibrosis Cardiac fibrosis was demonstrated to be significantly induced by the administration of streptozotocin (STZ) in a diabetic animal model [4]. ese studies have indicated that oxidative stress plays a critical role in the diabetic induction of myocardial fibrosis
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