Intermittent Hypoxia Induces Epigenetic Changes and P16-mediated Senescence in Left Cardiac Ventricle and Aorta Which Are Associated With Vascular Dysfunction

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Abstract INTRODUCTION/RATIONALE: Epidemiologic and intervention-based studies indicated a causative link between Obstructive Sleep Apnea (OSA) and cardiovascular disease (CVD). However, the molecular and cellular mechanisms involving OSA and CVD are still poorly understood. We aimed to investigate epigenetic changes and the role of p16-mediated cellular senescence in the left ventricle and aorta of mice exposed to chronic intermittent hypoxia (IH) as a model of OSA.METHODS: C57Bl/6 mice were exposed to IH (21% FIO2 and 6.1% FIO2; 20 cycles/h for 12 h/day) or room air (RA, continuous 21% FiO2) conditions for 7,14, 30, 120 and 210 days. At each time point, n=5 animals/group were sacrificed, and left cardiac ventricle was collected. DNA methylation profiles were analyzed and statistically significant differentially methylated loci (DML, Absolute FC > 2 and corrected p-value < 0.05), DML-associated pathways, and tissue-specific epigenetic age were assessed. Transgenic reporter mice (p16-CreERT2- tdTomato mice) were used to study the effect of IH on p16-mediated senescence, and p16 DNA methylation and expression. A second transgenic mouse (p16-CreERT2-DTR-tdTomato) was used to study the molecular and physiological effects of selective elimination of p16(+) cells. p16 gene expression and DNA methylation were assessed in cardiac left ventricle, aortic arches and aortas by Immunofluorescence and qPCR methods, respectively. RESULTS: IH induced significant differences (p<0.05) in tissue-specific age acceleration in the left cardiac ventricle compared with RA controls at all time points. Regression models revealed n=5,747 DML significantly associated with IH exposures (q<0.05). Pathway analysis demonstrated enrichment of pathways related inflammation and oxidative stress and highlighted IH-induced epigenetic changes in genes regulating cellular senescence. Among them, the promoter of the p16 gene showed a significant reduction in DNA methylation in IH (log2FC=0.022, p=0.003). Further analysis demonstrated significant p16 differential methylation in the aortic arch and aorta between IH and RA groups (p<0.05). In vivo assessment revealed that IH increased p16 expression in endothelial cells (p=0.029) but not in smooth muscle (p=0.282). p16(+) cell ablation affected only endothelial cells (p=0.017 and 0.232, for endothelial and smooth muscle cells, respectively). Moreover, ablation of p16(+) cells significantly reduced mean blood pressure and increased coronary flow reserve (p<0.05).CONCLUSIONS: The adverse effects and underlying contributions of epigenetics and senescence in OSA-induced cardiovascular dysfunction, including the left ventricle, aortic arch and aorta, emerge as possible therapeutic targets for OSA-induced CVD.

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