OLMESARTAN FOR IMMUNE MODULATION AND ATTENUATION OF MYOCARDIAL FIBROSIS IN OBESITY-INDUCED CARDIAC DYSFUNCTION

Objective: Obesity-induced myocardial fibrosis is a major contributor to diastolic dysfunction and, ultimately, heart failure. This study investigated the therapeutic potential of Olmesartan, an angiotensin II receptor blocker, using both in vivo and in vitro models.Design and method: Spontaneously hypertensive rats (SHR) were divided into three groups: SHR-CHO (chow diet, n=10), SHR-HFD (high-fat diet, n=10), and SHR-HFD-O (high-fat diet with Olmesartan treatment, n=10). Additionally, an in vitro model was employed to evaluate the effects of Olmesartan on TGF-β1-induced fibrosis in rat cardiac fibroblasts. Results: In vivo, Olmesartan significantly reduced systolic blood pressure, improved glucose tolerance, and normalized lipid profiles compared to SHR-HFD. Echocardiographic assessments revealed enhanced left ventricular diastolic function and reduced wall thickness in the SHR-HFD-O group. Histological analyses demonstrated a marked attenuation of perivascular and interstitial fibrosis, supported by reduced expression of fibrotic markers such as collagen type III and TGF-β1. Olmesartan also modulated macrophage polarization in pericardial fat, shifting from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes, as demonstrated by immunofluorescence and immunohistochemistry. Furthermore, regulatory T cell populations were restored in mesenteric lymph nodes, indicating an immunomodulatory effect. In vitro, rat cardiac fibroblasts stimulated with TGF-β1 exhibited an upregulation of fibrotic markers, which were significantly suppressed by Olmesartan treatment. Western blot and real-time PCR analyses confirmed the downregulation of collagen type III and TGF-β1 expression, indicating that Olmesartan inhibits key fibrotic signaling pathways at the cellular level. Conclusions: In conclusion, Olmesartan exhibited significant protective effects against obesity-induced cardiac and metabolic dysfunctions by acting through hemodynamic, metabolic, and immunomodulatory mechanisms.