Comparative Efficacy of β-Carotene and Losartan Against Isoproterenol-Induced Cardiac Fibrosis: An Experimental and Computational Studies.

Abstract

Objective: β-carotene, a vitamin A precursor is reported to inhibit molecular pathways cardinal to pathogenesis of fibrotic tissue alterations and in this study, the effectiveness of 14 days oral administration of β-carotene (10, 20, and 40 mg/kg/day) in the cardiac fibrosis (CF) in rats was studied and explored the mechanisms through network pharmacology.

Methods: CF was induced by isoproterenol (ISO) 6 mg/kg/SC from day 1 to day 7. Losartan (LOS) 10 mg/kg/day/p.o. served as the standard. Both β-carotene and LOS were administered from day 1 to 14. On the 15^th day, ECG and blood pressure (systolic, diastolic and mean) were recorded in the anesthetized rats followed by their euthanasia. The extent of cardiac fibrosis in the isolated hearts was determined using heart coefficient, tissue levels of hydroxyproline, histological examination. The oxidative stress in cardiac tissue was estimated, as GSH, SOD, catalase, MDA and NO. β-carotene targeted proteins pathway, process, and functional enrichment analysis were explored through network pharmacology.

Results: β-carotene dose-dependently mitigated the biochemical and histological changes induced by ISO in heart tissues. In ECG, it restored ST height, QT, and QRS intervals. Additionally, it normalized systolic, diastolic, and mean arterial pressures. The reduction in heart coefficient suggests β-carotene's potential to inhibit collagen deposition in heart tissue. β-carotene normalized oxidative stress markers, and hydroxyproline levels. All other biochemical parameters were restored to normal levels with β-carotene treatment. β-carotene 40 mg/kg dose showed comparable effect to that of LOS 10 mg/kg. β-carotene modulated IL-17, TNF, NF-kappa B, HIF-1, Sphingolipid, Relaxin, Adipocytokine, cAMP, Toll-like receptor, MAPK, PI3K-Akt, cGMP-PKG, VEGF, Ras, and PPAR signaling pathways.

Conclusions: β-carotene dose-dependently protects against ISO-induced CF in rats, with 40 mg/kg as an effective antifibrotic dose.