Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia

Abstract

More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1β, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

Occlusion preconditioned mice are resilient to hypobaric hypoxia-induced myocarditis and arrhythmias due to enhanced immunomodulation, metabolic homeostasis, and antioxidants defense

“…Also, disruption in redox homeostasis is a cofactor in HH-induced cardiac dysfunction ( 7 ), and our findings consolidated this fact, as HIF-1α, HIF-2α and Nrf2 expression were declining in HH mice hearts. Even so, it was observed that by employing OP intervention, HIF-2α and Nrf2 but not HIF-1α expressions were rescued and sustained in OPHH mice hearts.…”

“…Redox homeostasis (balance between ROS and antioxidants) signaling are major alterations occurring during chronic hypoxia ( 7 ). Hence, to elucidate the underlying mechanisms employed by the OP intervention during HH, we investigated its impact on oxidative stress regulators – hypoxia-inducible factors (HIF-1α and HIF-2α) and antioxidant response element-dependent genes regulator, nuclear factor erythroid 2–related factor 2 (Nrf2).…”

“…Also, the possibility of HH at such altitudes to induce or aggravate myocarditis, arrhythmia, and ultimately heart failure due to adverse cardiac remodeling has made clinicians to advised those prone to cardiovascular complications and physiologically unprepared individuals against visiting high altitudes ( 25 – 27 ). Studies over the years have made attempts at elucidating the underlying pathomechanisms of altitude sickness and have generally demonstrated that the clinical manifestations observed are due to HH-induced maladaptive oxidative stress responses (imbalance between ROS and antioxidants), metabolic dysregulation and dampened anti-inflammatory defenses ( 7 , 28 , 29 ). Currently, AP and salidroside are the primary preventive therapeutic interventions being employed to circumvent or mitigate the adverse effects of HH exposure.…”

“…Therapeutic approaches developed against altitude sickness over the years have mainly been preventive interventions targeted at circumventing or mitigating the adverse outcomes of HH exposure. Notably, the use of salidroside (a phenylethanoid glycoside found in Rhodiola genus plants) and altitude preconditioning (AP) (as known as intermittent HH preconditioning) prior to visiting high altitudes have been extensively shown to exert cardioprotective effects ( 6 , 7 ). The efficacies of salidroside and AP interventions have been attributed to their abilities to decrease reactive oxygen species (ROS), induce adaptive regulation of antioxidants and anti-inflammatory-related pathways as well as enhance tissue oxygenation to prevent necrosis and apoptosis of cardiomyocytes ( 6 – 9 ).…”

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

“…Mild hypoxic preconditioning has become a novel therapeutic target in the treatment of hypertension [ 108 ], myocardial infarction [ 109 ], cerebral ischemia [ 110 ], and depression [ 111 ]. It is even proposed as a potential application for patients with COVID-19 [ 112 ].…”