Therapeutic Effect of Rosolic Acid against Endothelial Dysfunction inDiabetic Wistar Rats

Introduction: Endothelial dysfunction (ED) results from impaired vascular endothelial cell function, disrupting key processes such as hemostasis, vascular tone regulation, vasculogenesis, angiogenesis, and inflammation. These processes are mediated by a complex signaling network involving hormones, cytokines, and chemokines. ED is recognized as a major contributor to the onset and progression of several micro- and macrovascular diseases, including diabetes. Our previous study demonstrated that the polyphenol Rosolic acid (RA) protects against ER stress-induced ED in vitro by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, RA enhanced the proliferation and survival of pancreatic β-cells in a co-culture model with endothelial cells under ER stress conditions. Methods: In this study, we investigated RA's protective effects against diabetes-induced ED using high-fat diet (HFD)-fed and streptozotocin-induced type-2 diabetic rat models. We evaluated RA’s impact on vascular function and metabolic parameters in these models. Results: RA significantly mitigated diabetes-induced ED in the aortic tissues of HFDfed diabetic Wistar rats. RA treatment improved glucose tolerance and reduced hyperlipidemia, showing efficacy comparable to the anti-diabetic drug Gliclazide. Moreover, RA elevated Nrf2 levels and its downstream target genes in aortic tissues while reducing ED markers such as ICAM-1, VCAM-1, and endothelin-1. Conclusion: These findings highlight RA as a promising therapeutic agent for diabetes and its associated vascular complications, with potential for broader clinical applications.