Pathophysiological implications of hypoxia in human diseases - PubMed (original) (raw)

Review

Pathophysiological implications of hypoxia in human diseases

Pai-Sheng Chen et al. J Biomed Sci. 2020.

Abstract

Oxygen is essentially required by most eukaryotic organisms as a scavenger to remove harmful electron and hydrogen ions or as a critical substrate to ensure the proper execution of enzymatic reactions. All nucleated cells can sense oxygen concentration and respond to reduced oxygen availability (hypoxia). When oxygen delivery is disrupted or reduced, the organisms will develop numerous adaptive mechanisms to facilitate cells survived in the hypoxic condition. Normally, such hypoxic response will cease when oxygen level is restored. However, the situation becomes complicated if hypoxic stress persists (chronic hypoxia) or cyclic normoxia-hypoxia phenomenon occurs (intermittent hypoxia). A series of chain reaction-like gene expression cascade, termed hypoxia-mediated gene regulatory network, will be initiated under such prolonged or intermittent hypoxic conditions and subsequently leads to alteration of cellular function and/or behaviors. As a result, irreversible processes occur that may cause physiological disorder or even pathological consequences. A growing body of evidence implicates that hypoxia plays critical roles in the pathogenesis of major causes of mortality including cancer, myocardial ischemia, metabolic diseases, and chronic heart and kidney diseases, and in reproductive diseases such as preeclampsia and endometriosis. This review article will summarize current understandings regarding the molecular mechanism of hypoxia in these common and important diseases.

Keywords: Cancer; Cardiomyopathy; Chronic kidney disease; Endometriosis; Hypoxia; Metabolic diseases; Preeclampsia.

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Conflict of interest statement

All authors declare there is no conflict of interest.

Figures

Fig. 1

Fig. 1

Schematic diagram illustrates the regulation of HIF-1α and NF-κB under normoxic and hypoxic conditions

Fig. 2

Fig. 2

Hypoxia-regulated cancer progression. Hypoxia is a typical feature of tumor microenvironment, which contributes to initial tumorigenesis, induced angiogenesis, drug resistance, and cancer metastasis. The major upstream regulators (gray), functional downstream genes (blue), and resulting cellular consequences (yellow) under the control of hypoxia signaling are indicated

Fig. 3

Fig. 3

Hypoxia-regulated lipid metabolism related to obesity. Hypoxia is shown as a promoter or a suppressor of obesity by regulating lipid metabolism. The major changes (increases shown in red; decreases shown in green) involved in fatty acid β-oxidation, extracellular fatty acid influx, lipolysis, lipogenesis and lipid droplet accumulation under hypoxia for its promoting obesity or anti-obesity effects are summarized

Fig. 4

Fig. 4

Schematic diagram of the hypoxic process linked to kidney diseases. During the development of CKD, vascular endothelial cells died and causing atrophy of microvessels. This will cause local hypoxia between tissues and cause inflammatory reactions. Hypoxia induces the expression of TGF-β, which leads to fibroblast transformation into myofibroblast, increases ECM production, and causes fibrosis. Renal tubular epithelial cells may encounter cell cycle arrest, apoptosis, autophagy, and finally shrink during renal fibrosis

Fig. 5

Fig. 5

Potential role of hypoxia in developing preeclampsia. Binding of EG-VEGF to its receptor on the primary cilium activates ERK signaling at the basal body for proper placentation. Under hypoxic condition, however, HIF-1α translocates to the base of cilia and induces cilia deacetylation, thus leading to ciliary resorption. The hypoxia-induced ciliary defects contribute to the development of preeclampsia

Fig. 6

Fig. 6

Impacts of hypoxia on endometriosis pathogenesis. Shed-off endometrial tissues will immediately suffer hypoxic stress when it retrogrades into the peritoneal cavity during menstruation. Hypoxia regulates numerous downstream target genes involved in different cellular processes including cell survival, metabolism, angiogenesis, E2 and PGE2 production, and cell adhesion to help the development of endometriosis

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