Mechanistic pathways of coumarins-mediated cardioprotection: From antioxidant activity to endothelial modulation

Coumarins are naturally occurring benzopyrones widely recognized for their antioxidant, anti-inflammatory, and vasomodulatory properties. Emerging evidence highlights their potential role in preventing and mitigating cardiovascular injury through integrated modulation of redox balance, nitric oxide (NO) signaling, and endothelial function. This review consolidates preclinical and mechanistic data derived from in vitro and in vivo studies addressing the cardioprotective effects of coumarins. Emphasis was placed on experimental models of ischemia-reperfusion, oxidative stress, and drug-induced cardiotoxicity. Molecular targets were analyzed to elucidate pathways linked to redox modulation, NO synthesis, and inflammatory cascades. Coumarins have been shown in experimental models to scavenge reactive oxygen species, enhance endogenous antioxidant enzyme activity, and preserve mitochondrial integrity. They have also been reported to activate endothelial nitric oxide synthase, increase vascular NO bioavailability, and suppress the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin. Furthermore, coumarins modulate NF-κB and NLRP3 inflammasome signaling, contributing to reduced TNF-α, IL-1β, and IL-6 levels in cardiac tissues under experimental conditions. Preclinical studies demonstrate improvements in myocardial architecture, reductions in serum cardiac injury markers, and enhanced vascular perfusion following coumarin-type treatment in animal models. Although coumarins have demonstrated acceptable safety profiles in several experimental models, concerns regarding dose-dependent hepatotoxicity and the limited availability of robust human safety data warrant cautious interpretation and careful therapeutic evaluation. Collectively, current evidence suggests that coumarins may exhibit multitarget cardioprotective properties mediated through integrated antioxidant, anti-inflammatory, and endothelial-modulatory mechanisms. However, well-designed clinical studies are required to validate these findings and define their translational applicability in cardiovascular therapy.