Intermittent hypoxia induces premature adipose tissue senescence leading to cardiac remodelling

Abstract

Obstructive sleep apnea is a growing health problem effecting almost 1 billion world population presently. The landmark feature of OSA is a chronic intermittent hypoxia (CIH) responsible for multiple organ damages including heart diseases. CIH profoundly alters both visceral white adipose tissue (vWAT) and heart structures and functions, but little is known regarding their interactions in the context of CIH. We recently showed that vWAT senescence drives myocardial alterations through the release of profibrotic factors in aged mice. We aim at demonstrating that CIH induces a premature vWAT senescent phenotype, responsible for subsequent heart dysfunction In a first experiment, ten-weeks old C57BL6 male mice ( n = 10/group) were exposed to 14 days CIH protocol (8 hours daily, 5–21% cyclic inspired oxygen fraction, 60 seconds per cycle). In a second series, mice were submitted to either vWAT surgical lipectomy or sham-surgery. Finally, we used p53 KO mice or littermates, also exposed to the same CIH protocol. vWAT and hearts were assessed for fibrosis, hypertrophy, DNA damage, oxidative stress, markers of senescence (p16, p21, p53) and inflammation by histology, RT-qPCR and western blot. CIH induced a “senescent-like” phenotype in vWAT, characterized by increased fibrosis, oxidative stress, DNA damage and inflammation (macrophage infiltration and inflammatory markers expression). This was associated with CIH-induced myocardial interstitial fibrosis and upregulation of profibrotic gene expression in myocardium. Interestingly, CIH did not induce vWAT remodeling in p53KO mice and CIH-induced myocardial interstitial fibrosis was prevented by both vWAT resection and p53 deletion. Short-term exposure to CIH is sufficient to induce vWAT premature senescence and cardiac interstitial fibrosis that was prevented by vWAT lipectomy and deletion of p53 senescence pathway. This strongly suggest a causal crosstalk between CIH-induced vWAT senescence and cardiac remodelling.