Protection against Hypobaric Hypoxia-induced Cardio-pulmonary Damaging Effects via Modulating the ACE2 / AT (1-7) axis using Nanocurcumin Formulation

Introduction: Hypobaric hypoxia (HH) is a high-altitude condition causing chronic cardiopulmonary damage due to an imbalance between the classical and non-classical RAAS axis. Previous research has shown that nanocurcumin formulation (NCF) significantly protects against cardio-pulmonary damage and right ventricular hypertrophy in rodent models under HH conditions. In this study, the NCF was evaluated as a cardio-pulmonary protective agent acting on the Renin-Angiotensin-Aldosterone System (RAAS) pathway axis in rats under HH. Methods: The Sprague Dawley rats were exposed in a simulated HH chamber at 282 torr for 7 and 14 days (Temp-25°C; humidity- 55 %). After HH-exposure, lungs and heart tissue were excised, snap frozen, and stored at -80°C till further analysis. Results: The present study revealed an increased (p< 0.01) expression of classical RAAS axis marker (angiotensin converting enzyme and angiotensin-II) while reducing non-classical RAAS axis marker (angiotensin converting enzyme 2 and angiotensin 1-7), resulting elimina-tion of counterbalance activity upon angiotensin-II (AT-II). Further increased level of AT-II significantly (p< 0.01) intensifies the release of pro-inflammatory cytokines (IFN-γ, IL-6, and TNF-α) following NF-κBp65 translocation into the nucleus. Interestingly, NCF treatment in-creased (p< 0.05) expression of non-classical RAAS axis markers with concomitant decline (p< 0.05) of the classical RAAS axis markers. discussion: The renin-angiotensin-aldosterone system (RAAS) is involved in lung pathophysiologies like idiopathic pulmonary fibrosis, sarcoidosis, and COVID-19. Supplementation with NCF during hypoxia exposure reduces ACE and ang-II expressions, improves cardiopulmonary adaptation, and modulates VEGF expression. NCF, an NF-κB inhibitor, protects against inflammation and lung injury, reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Discussion: NCF supplementation during hypoxia reduces ACE and ang-II expressions, im-proves cardiopulmonary adaptation, and modulates VEGF expression, protecting against in-flammation and lung injury through NF-κB inhibition. Conclusion: NCF's modulatory and anti-inflammatory effects in the RAAS axis in HH-ex-posed animals may alleviate post-COVID cardiopulmonary damage, making it a potential op-tion for managing post-COVID inflammatory complications.