Cornus officinalis total glycosides modulate inflammatory response and inhibit the JAK1/STAT3 pathway within a preclinical rat model of cardiac ischemia/reperfusion-induced injury.

Abstract

OBJECTIVE: Cardiac ischemia/reperfusion (I/R) injury is characterized by excessive inflammation and aberrant activation of intracellular signaling pathways, including JAK/STAT. Cornus officinalis total glycosides (COTG) possess anti-inflammatory properties, but their role in myocardial I/R injury remains incompletely defined. This study aimed to investigate the cardioprotective effects of COTG against I/R -induced injury and clarify its pathway-dependent mechanism involving JAK1/STAT3 signaling. METHODS: A myocardial I/R injury model was established in male Sprague-Dawley rats, which were randomly divided into Sham control, I/R control, and COTG-treated groups (200, 400, and 600 mg/kg). Cardiac function was evaluated by echocardiography, and myocardial histopathology was assessed by hematoxylin and eosin staining. Serum myocardial injury markers were measured by ELISA. Inflammatory cytokine expression and macrophage polarization were analyzed using qRT-PCR and immunofluorescence, respectively. JAK1/2 and STAT3 phosphorylation was detected by Western blotting. An in vitro hypoxia/reoxygenation (H/R) model combined with a pharmacological JAK inhibitor was further employed to verify pathway dependency. RESULTS: COTG treatment significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction and fractional shortening and reduced ventricular dilation. Histological damage and serum levels of cardiac troponin I, cardiac troponin T, and creatine kinase-MB were markedly attenuated. COTG suppressed pro-inflammatory markers (iNOS, IL-1β, IL-6) while enhancing anti-inflammatory mediators (Arg-1, IL-10). Mechanistically, COTG dose-dependently inhibited JAK1, JAK2, and STAT3 phosphorylation without altering total protein levels. Pharmacological inhibition experiments confirmed that JAK/STAT suppression by COTG was pathway-dependent. Moreover, COTG reduced myocardial apoptosis by increasing Bcl-2 and decreasing Bax and cleaved caspase-3 expression. CONCLUSION: COTG protects against myocardial I/R injury by pathway-dependent inhibition of JAK/STAT signaling, modulation of inflammatory responses, and attenuation of cardiomyocyte apoptosis, highlighting its therapeutic potential for ischemic heart disease.