Cardioprotective effects of subacute inosine administration in a hypercholesterolemic model: role of Nrf2 and calcium signaling

Introduction: Inflammation-induced oxidative stress under hypercholesterolemic conditions is closely related to myocardial dysfunction. Recent studies have shown that NMDA receptors and calcium signaling participate in myocardial dysfunction through ROS production and apoptosis (Front. Cardiovasc. Med. (2022) 9.837142). Inosine presents vascular protective effects under hypercholesterolemic conditions (Eur. J. Pharmacol. (2020) 882:173289). The present study aims to evaluate the cardiac properties of inosine in a hypercholesterolemic model.

Methodology: The animal protocols were approved by the Ethics Committee for Experimental Research of the Federal Fluminense University (CEUA/UFF 1479140219). Wistar rats (250-300g) were randomly divided in control group (C) and control group + inosine (C+I) fed standard chow diet, hypercholesterolemic group (HC) and hypercholesterolemic group + inosine (HC+I). Subacute treatment with inosine (10mg/kg/orally) was performed at day 31, once daily, for 15 days. At the end of the experimental protocol, rats were submitted to echocardiography and electrocardiography analysis and samples were collected for biochemical and molecular analysis.

Results: We observed that HC diet leads to a reduction in eject fraction and increase in internal diameter of the left ventricle, posterior wall of the left ventricle, QRS and QTc interval. Furthermore, we also observed an increase in calcium handling proteins expression like NMDAR1, LTCC and IP3R, apoptosis markers as BAX and Caspase-3, and Nrf2 inhibition (p<0,05). On the other hand, inosine was able to revert those effects on eject fraction, QRS duration, calcium-related proteins, apoptosis and antioxidant pathway (p<0.05).

Conclusion: Inosine presented cardioprotective effects through the regulation of calcium homeostasis, apoptosis and antioxidant capacity. This study provides evidence that indicate inosine as a potential drug for the treatment of hypercholesterolemia-induced cardiac damage.