Abstract
High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.
Highlights
Many people are exposed to high altitudes, where more than 140 million of them live permanently at an elevation > 2500 m above sea level, and approximately 40 million individuals are exposed to high altitudes for hours or days [1]
In recent years, a new condition associated with high altitude has been reported in South America as long-term chronic intermittent hypobaric hypoxia; this type of exposure refers to people commuting to work at high altitudes for several days and returning to sea level to rest for the same number of days for years
Hypoxia exposure produces an alteration of protein kinase C (PKC), considered a key regulator in pressure overload (PO)-induced cardiac hypertrophy, and its activation can be modulated by reactive oxygen species (ROS) derived from mitochondrial complex III [68]
Summary
Many people are exposed to high altitudes, where more than 140 million of them live permanently at an elevation > 2500 m above sea level, and approximately 40 million individuals are exposed to high altitudes for hours or days [1]. Cardiac hypertrophy is defined as an enlargement of the heart wall with an increase in the volume of cardiomyocytes; there are two forms of cardiac hypertrophy, namely, physiological, as occurs in response to exercise, and pathological, as occurs in response to abnormal stress, such as hypertension, pressure overload, endocrine disorders, myocardial infarction, and contractile dysfunction from inherited mutations in sarcomeric or cytoskeletal proteins [15,16] This acclimatization response allows normal wall stress function, preserving right ventricle (RV) function, but in the long term, this acclimatization hypertrophy mechanism is overrun; contractile dysfunction and RV dilatation occur, with a subsequent increase in wall stress that stimulates further hypertrophy, leading to a vicious cycle in the impairment of RV performance, which derives in RV failure and eventually leads to death [17,18,19]. The aim of this review is to describe and update the knowledge on the molecular pathways involved in RVH and RHF under hypobaric hypoxia, including oxidative stress, protein kinase activation and inflammatory processes, as well as the current therapeutic approaches for these conditions
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