Ferulic Acid Suppresses Diabetes‐Induced Atherosclerosis by Targeting Oxidative Stress, NF‐κB p65/iNOS, and miRNAs Pathways

Abstract

Atherosclerosis, a major complication of diabetes mellitus, involves complex metabolic and inflammatory disruptions that remain inadequately addressed by current therapies. Ferulic acid (FA), a plant-derived polyphenol, possesses antioxidant and anti-inflammatory characteristics, yet its role in diabetic atherosclerosis remains underexplored. In the current study, we explore the anti-atherosclerosis effects of FA against diabetes-induced atherosclerosis in rats. Forty male Wistar rats received a high-fat diet, streptozotocin, and vitamin D3 to induce atherosclerosis. Rats were divided into control, atherosclerotic, and treated with FA (50 mg/kg, daily for 7 weeks as preventive and 3 weeks as therapeutic) or rosuvastatin (5 mg/kg, daily for 7 weeks). Body weight, biochemical, molecular, and histopathological analyses were conducted. Atherosclerotic rats exhibited significant hyperglycemia, dyslipidemia, inflammation, and vascular injury. FA administration obviously improved body weight, fasting and postprandial glucose levels, lipid profile, and cardiovascular indices. Moreover, FA significantly reduced serum oxLDL, MDA, and NO levels, while it significantly increased serum activities of both SOD and GPX, besides GSH levels. FA treatment significantly downregulated NF-κB p65, iNOS, and MMP-9 aortic protein levels. Additionally, serum pro-inflammatory cytokines (TNF-α and MCP-1) were reduced, while serum levels of anti-inflammatory IL-10 were improved in FA-treated atherosclerotic rats. Serum miR-27 and miR-29 expression levels were significantly modulated after treatment with FA. The overall results suggested that FA confers multi-targeted protection against diabetic atherosclerosis through modulation of metabolic, oxidative stress, inflammatory, and epigenetic pathways. These findings highlight its potential as a complementary or preventative approach in the management of vascular diseases associated with diabetes.