Phosphodiesterase inhibitor, Vinpocetine, guards against doxorubicin induced cardiotoxicity via modulation of HIF/VEGF and cGMP/cAMP/SIRT signaling pathways

Abstract

Purpose: Doxorubicin (DOX) is a widely used chemotherapeutic agent complicated with cardiotoxic adverse effects. Up till now, there are no researches discussing the role of vinpocetine (VIN) in DOX cardiotoxicity. Thus, the aim of our work was to study this effect and explore the different involved mechanisms. Methods: 50 male Wistar albino rats were subjected to DOX toxicity via administration of single i.p. Dose (15 mg/kg) on the 4th day with or without co-administration of VIN (10, 20, 30 mg/kg/day) orally for 5 days. Results: Our data revealed that VIN succeeded in protecting the heart against DOX induced damage as manifested by significant decrease of cardiac enzymes, hypoxia inducible factor alpha (HIF-1α), vascular endothelial growth factor-A (VEGF-A), tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and caspase3 levels. Furthermore, VIN given group showed marked improvement of the histopathological changes of cardiac injury, total antioxidant capacity (TAC), elevation of reduced glutathione (GSH), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT-1). Conclusion: We concluded that VIN could ameliorate DOX induced cardiac damage and this effect may be attributed to modulation of HIF/VEGF signaling pathway, up-regulation of cGMP/cAMP/SIRT pathway, inhibition of phosphodiesterase enzyme, besides its anti-apoptotic, anti-inflammatory, and anti-oxidant properties.

FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM

“…A miR-4732-3p mimic was also proved to be cardioprotective in cardiac and fibroblast cultures following DOX challenge, via regulating genes of TGFβ and Hippo signaling pathways [ 53 ]. Moreover, vinpocetine, a phosphodiesterase inhibitor, was found to guard against DOX-induced cardiotoxicity as manifested by a significant decrease of cardiac enzymes, HIF-1α and TNF-α, via modulation of HIF/VEGF and cGMP/cAMP/SIRT signaling pathways [ 54 ]. Nicotinamide riboside administration was shown to exert a cardioprotective property against chronic DOX-induced cardiomyopathy [ 55 ].…”

“…and TNF-α, via modulation of HIF/VEGF and cGMP/cAMP/SIRT signaling pathways [54]. Nicotinamide riboside administration was shown to exert a cardioprotective property against chronic DOXinduced cardiomyopathy [55].…”

Azilsartan improves doxorubicin-induced cardiotoxicity via inhibiting oxidative stress, proinflammatory pathway, and apoptosis

“…These findings align with numerous previous studies indicating that DOX-induced free radicals deplete the antioxidant glutathione and lead to the overutilization of cardiac antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Such oxidative stress could account for the observed reduction in total antioxidant capacity [21][22][23]. The well-estab-matory response, inducing the production of cytokines, chemokines, and other proinflammatory mediators [16].…”