Chronic intermittent hypoxia leads to disruption of clock genes expression in mouse lung tissues: Potential consequences on lung cell senescence - 20/03/24

Obstructive sleep apnoea (OSA) syndrome is a common sleep disorder in which recurrent apnoea and hypopnoea produce repeated episodes of hypoxemia followed by reoxygenation. We previously demonstrated that OSA was associated with telomere shortening and increased susceptibility to cell senescence [1Boyer, y al. Ann Am Thorac Soc 2016 ;  13 : 1136-1143 [cross-ref]

Haga clic aquí para ir a la sección de Referencias]. The cyclin-dependent kinase inhibitor p21, the main effector of p53, is activated in response to DNA damage and telomere dysfunction but is down-regulated by certain clock genes. Sleep abnormalities also disrupt endogenous circadian clock genes, more specifically Rev-Erbα, a central transcriptional repressor of the molecular clock that downregulates p21 expression.

Here we investigated the effect of chronic intermittent hypoxia (CIH), a model of OSA, on lung cell senescence induction in mice. To this end, we exposed 2-month-old c57/bl6 mice to CIH (8hours a day) for one to 21 days and harvested lungs for histological and biological analyses, the day after CIH was stopped.

We found that the rhythmicity of the canonical clock genes Rev-Erbα, Rev-Erbß and Bmal-1 was associated with a rhythmicity of lung p21 during normoxia, with opposite variations of Rev-Erbα and p21. Exposure to CIH lead to an increase in Rev-Erbα at ZT 2-4 (morning) compared to normoxia, together with a downregulation of p21, observed either after 1.2, 7, or 21 days of CIH exposure, and lasting longer than 48hours after return to normoxia. No changes were observed at later time of the day. Consistent with this, senescence markers, including p16 and SASP components, were not affected by exposure to CIH. Similar changes were observed in aged (18-month-old) mice. Bulk RNA sequencing performed 3 weeks after CIH confirmed dysregulation of circadian clock and clock-controlled genes (Dbp, Rev-Erbα, Hlf) together with an increase in several collagen transcripts. Treatment of the mice with a Rev-Erbα antagonist (SR8278), partially restored the reduction in p21 expression after one day CIH, pointing toward a causal link between changes in lung Rev-Erbα and p21 during CIH. Interestingly, mice exposed to 21 days and even to 35 days CIH did not develop lung structural alterations, potentially as a consequence of a protection afforded by p21 downregulation and protection against cell senescence. Studies are underway to assess the consequences of CIH exposure in Rev-Erbα and Bmal-1 deficient mice.

Our data indicate that CIH has a major impact on clock genes expression, which may in turn play a protective role against cell senescence.