Involvement of hypoxia-inducible factor1-alpha in the protective effect of rivaroxaban against testicular ischemia-reperfusion in rats

Abstract

This study investigated the protective effects of Rivaroxaban (RVX) against testicular ischemia-reperfusion (IR) injury in rats with a secondary aim of studying the involvement of hypoxia-inducible factor1-alpha testicular protection against ischemic insults. Twenty-four male rats were divided into four groups: sham control, testicular IR, and two RVX treatment groups (7 and 14 mg/kg) administered for one week prior to IR. Testicular IR led to significant impairment in testicular function, evidenced by an 86.5% reduction in testosterone levels and marked oxidative stress with an 189.3% increase in malondialdehyde (MDA). IR injury also triggered substantial elevations in apoptotic markers (271% increase in Bax (Bcl2-associated X protein) and 65.9% decrease in BCL2 (B-cell lymphoma 2), and inflammatory mediators (285.7% increase in NFκB (nuclear factor-kappa B). Additionally, angiogenic markers showed dramatic increases, with VEGF (vascular endothelial growth factor) and HIF-1 (Hypoxia inducible factor-1) rising by 431.8% and 519%, respectively. RVX treatment demonstrated dose-dependent protective effects, with the 14 mg/kg dose showing superior outcomes compared to 7 mg/kg. The higher dose significantly improved hormonal function (486.8% increase in testosterone), reduced oxidative stress (51.8% reduction in MDA), modulated apoptotic markers (68.3% decrease in BAX, 159.1% increase in BCL2), and normalized angiogenic factors (71.8% reduction in HIF-1). In conclusion, RVX demonstrated significant therapeutic potential in protecting against testicular IR injury, with the 14 mg/kg dose showing optimal protective effects. Reduction in HIF-1α and VEGF protein expression mediated RVX’s anti-oxidant, anti-inflammatory, and anti-apoptotic effect in rats subjected to testicular IR.