Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases

Abstract

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Keywords: circadian cycle; genes; hypoxia; idiopathic pulmonary fibrosis; lung diseases.

Figure 2

The molecular circadian clock involves an autoregulatory loop encompassing the transcription activators BMAL1, CLOCK and/or NPAS2, regulated by the repressors Per and CRY. During hypoxia, HIF-1α and HIF-2α activation increases. These molecules have a dual regulation: HIF-1α and BMAL1 bind together to clock gene promoters, while clock proteins bind to the promoter of HIF-1α. Per3 levels were found to be diminished in asthma. BMAL1 levels seem to be diminished in animal models or patients with asthma, COPD, or LC and are also diminished by CS exposure; inhibition of or decrease in BMAL1 can lead to an increase in IL-5 and IL-6 expression and in the number of eosinophils in the presence of asthma. COPD or CS exposure reduces SIRT1 expression, which regulates BMAL1 and PER2. Moreover, CS exposure in REV-ERBα KO mice increased the number of neutrophils and the expression of proinflammatory cytokines. In COPD, the levels of RORα, the counterpart to REV-ERBα and a regulator of BMAL1, are diminished. BMAL1 also regulates p53 expression, and PER binds to p53, regulating the stabilization and nuclear translocation of the protein. BMAL1 can also block the AKT signaling pathway, which is overactivated in lung cancer. Furthermore, the protein Sharp1 was shown to interact with HIF-1α to induce its proteasomal degradation and prevent its union with HIF-1β, which promotes the expression of metastatic genes. In IPF, the increment in REV-ERBα leads to ECM remodeling, and REV-ERBα suppression promotes fibroblast-to-myofibroblast differentiation. NRF2 is positively regulated by BMAL1-CLOCK, and NRF2 increases the expression of Gclm and Gsta3, proteins involved in glutathione metabolism. Additionally, Sharp1 expression is reduced in IPF. In OSA, HIFs are overactivated and increase the expression of Clock, BMAL1, and CRY2. A, asthma; COPD, chronic obstructive pulmonary disease; LC, lung cancer; IPF, idiopathic pulmonary disease; OSA, obstructive sleep apnea; O2, oxygen; BMAL1, brain and muscle ARNT-like 1; NPAS2, neuronal PAS domain protein 2; CLOCK, circadian locomotor output cycles kaput; PER, period; CRY, cryptochrome; SIRT1, sirtuin1; HIF, hypoxia-inducible factor; IL-5, interleukin 5; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; KC, keratinocyte chemoattractant; AKT, protein kinase B; ECM, extracellular matrix; NRF2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element.

Figure 1

The circadian rhythm is a biological process that runs in a 24 h cycle, regulated by the suprachiasmatic nucleus in response to light–dark external cues. Many physiological systems are regulated by the circadian rhythm through the activity of cortisol and melatonin, which fluctuate throughout the day. Pathological states of chronic hypoxia can disrupt the circadian rhythm.

Figure 3

Network biology of hypoxia and circadian rhythm genes. This network represents the interaction between the hypoxia and circadian rhythm genes (orange nodes) and the genes reported to be associated with hypoxia and circadian rhythm genes (white nodes). Each edge (green) represents an independent reported association by CTD (https://ctdbase.org/, accessed on 14 September 2023). BMAL1, FOXa2, CKIε, PER3, TIM, Clock, PER2-3, BHLHE40-41, REV-ERBα, and CRY1-2 are hubs in this network, while RORα stands alone.