Chronic intermittent hypoxia activates cardiac stress-responsive mechanisms in a murine model of sleep apnea: Cardioprotective effect influenced by age

Rationale: Chronic intermittent hypoxia (CIH) induced by repetitive collapse of upper airways in obstructive sleep apnea (OSA) is a major determinant in the cardiovascular morbidity associated with OSA and this effect is influenced by age. The objective of the present study was to assess the differential molecular mechanisms that delineate the cardiovascular remodeling induced by CIH according to mice age.

Methods: Two-month and 18-month old mice (N=10 each) were subjected to CIH or normoxia for 8-weeks. Total mRNA was extracted from fresh left ventricle myocardium and gene expression of 46 intermediaries that promote or decrease aging, oxidative stress and inflammation processes was measured by quantitative real time PCR.

Results: Young mice exposed to CHI exhibited a differential regulation of 28% genes, while 4% in aged mice. In young mice, CIH: 1) promoted an important anti-oxidative response with the up-regulation of the
nuclear factor erythroid-2 (Nrf2, 2.05-fold increase, p=0.002) and superoxide dismutase 2 (Sod2, 1.9-fold increase, p= 0.005); 2) increased the nutrient-signaling pathways insulin-like growth factor 1 (IGF-1, 1.4-fold increase, p=0.005) and mammalian target of rapamycin (mTORC, 1.8-fold increase, p=0.01), mechanism that promote a physiological heart growth; 3) upregulated gene expression of factor forkhead box O3 (FOXO3, 1.5-fold increase, p=0.003) and sirtuin4 (1.3-fold increase, p=0.003) and sirtuin7 (1.36-fold increase, p=0.006), key intermediaries involved in DNA repair and stability, stress resistance, and anti-aging actions. In an age-independent manner, CHI: 1) increased interleukine-33 expression (3-fold increase, p<0.001), cytokine with antihypertrophic, anti-fibrotic and anti-inflammatory effects in heart tissue; and 2) reduced cell senescence mediated by cyclin-dependent kinase inhibitor 1 (CDKN1a, reduction of 70%, p<0.001).

Conclusion: CIH activates stress-responsive mechanisms in young mice that promote cellular survival, genome stability and stress resistance mediated mainly by an antioxidant response and cell senescence reduction. The magnitude of the cardioprotective effect associated with CIH is influenced by age.

Acknowledgements: Supported by Fondo de Investigación Sanitaria (PI16/00483), Fondo Europeo de Desarrollo Regional (FEDER), Una Manera de Hacer Europa; the Spanish Respiratory Society (ID/144), Socitat Catalana de Pneumologia.

This abstract is funded by: Fondo de Investigación Sanitaria (PI16/00483), Fondo Europeo de Desarrollo Regional (FEDER), Una Manera de Hacer Europa; the Spanish Respiratory Society (ID/144), Socitat Catalana de Pneumologia