Estrés oxidativo dependiente de Nox2 y modulación antioxidante en la hipertrofiaventricular derecha inducida por hipoxia hipobárica intermitente crónica

Resumen

Chronic intermittent hypobaric hypoxia (CIHH) is an increasingly prevalent occupational exposure characterized by repetitive cycles of days hypoxia-induced high altitude and days of rest at sea level that promote pulmonary vascular remodeling, high-altitude pulmonary hypertension, and progressive right ventricular hypertrophy (RVH). Although RVH initially serves as a compensatory response to elevated pulmonary vascular resistance, prolonged exposure to CIHH may result in maladaptive remodeling, fibrosis, metabolic dysfunction, and eventual right ventricular failure. Among the molecular mechanisms involved, oxidative stress has emerged as a central driver of cardiopulmonary injury. Recent evidence identifies NADPH oxidase-2 (Nox2) as a major enzymatic source of reactive oxygen species (ROS) during CIHH. Beyond direct ROS generation, Nox2 functions as a redox signaling hub linking mitochondrial dysfunction, endothelial injury, inflammation, and hypoxia-responsive transcriptional pathways. Excessive Nox2 activation promotes lipid peroxidation, endothelial nitric oxide synthase (eNOS) uncoupling, contribution to hypoxia-inducible factor-1α (HIF-1α) stabilization, and activation of stress-sensitive kinases such as p38 mitogen-activated protein kinase (MAPK). Furthermore, Nox2-derived ROS interact with mitochondrial ROS through mechanisms of oxidase crosstalk, amplifying oxidative injury and sustaining pathological remodeling within both the pulmonary vasculature and the right ventricle. Despite strong mechanistic support for antioxidant therapy, clinical outcomes have remained inconsistent, likely due to limited bioavailability, pharmacokinetic constraints, and the inability of conventional antioxidants to inhibit upstream ROS-generating pathways. In this context, astaxanthin has emerged as a promising next-generation antioxidant owing to its high membrane affinity, modulation of Nox2 expression, preservation of mitochondrial integrity, and activation of endogenous antioxidant defenses through Nrf2-dependent signaling. This narrative review synthesizes current evidence regarding the role of Nox2-mediated oxidative stress in CIHH-induced RVH and discusses emerging redox-targeted therapeutic strategies aimed at mitigating hypoxia-associated non-compensatory cardiovascular remodeling.