Université Paris Est Créteil, INSERM U955, Créteil, France.
Université Grenoble Alpes, INSERM U1300, CHU Grenoble Alpes, HP2, Grenoble, France.
Acta Physiol (Oxf). 2024 Nov;240(11):e14231. doi: 10.1111/apha.14231. Epub 2024 Sep 12.
Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter-organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling.
In a first experiment, 10-week-old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%-21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild-type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT-qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy.
CIH-induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH-induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH-induced myocardial fibrosis.
Short-term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA-related cardiac disorders.
阻塞性睡眠呼吸暂停（OSA）是一种在全球范围内影响近 10 亿人的日益严重的健康问题。OSA 的标志性特征是慢性间歇性低氧（CIH），它会导致多个器官损伤，包括心脏病。CIH 深刻地改变了内脏白色脂肪组织（WAT）和心脏的结构和功能，但对于 CIH 背景下的器官间相互作用知之甚少。我们最近表明，在没有 CIH 的情况下，内脏 WAT 衰老会导致老年小鼠的心肌改变。在这里，我们旨在研究 CIH 是否会引起过早的内脏 WAT 衰老表型，从而引发随后的心脏重塑。
在第一个实验中，10 周龄的 C57bl6J 雄性小鼠（每组 10 只）接受 14 天的 CIH（每天 8 小时，5%-21%循环吸入氧分数，60 秒/周期）。在第二个系列中，在暴露于 CIH 之前，小鼠接受附睾 WAT 外科去脂术或假手术。最后，我们使用 p53 缺陷小鼠或也接受相同 CIH 方案的野生型（WT）同窝仔鼠。通过 RT-qPCR 和组织学评估附睾 WAT 的纤维化、DNA 损伤、氧化应激、衰老标志物（p16、p21 和 p53）和炎症，并评估心肌的纤维化和心肌细胞肥大。
CIH 诱导的附睾 WAT 重塑表现为纤维化、氧化应激、DNA 损伤反应、炎症和衰老标志物表达增加。CIH 诱导的附睾 WAT 重塑与微妙的早期心肌间质纤维化有关。附睾 WAT 外科去脂术和 p53 缺失均可预防 CIH 诱导的心肌纤维化。
短期暴露于 CIH 会引起附睾 WAT 衰老重塑和心脏间质纤维化，而外科去脂术可预防后者。这一发现强烈表明内脏 WAT 衰老作为减轻 OSA 相关心脏疾病的新靶点。
