Chronic Intermittent Hypoxia Regulates CaMKII‐Dependent MAPK Signaling to Promote the Initiation of Abdominal Aortic Aneurysm

Abstract

Obstructive sleep apnea (OSA) is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, the effects of OSA on AAA initiation in a murine model of sleep apnea have not been completely studied. In this paper, Apoe-/- C57BL/6 mice infused with angiotensin II (Ang II) were placed in chronic intermittent hypoxia (CIH) condition for inducing OSA-related AAA. CIH significantly promoted the incidence of AAA and inhibited the survival of mice. By performing ultrasonography and elastic Van Gieson staining, CIH was found to be effective in promoting aortic dilation and elastin degradation. Immunohistochemical and zymography results show that CIH upregulated the expression and activity of MMP2 and MMP9 and upregulated MCP1 expression while downregulating α-SMA expression. Also, CIH exposure promoted ROS generation, apoptosis, and mitochondria damage in vascular smooth muscle cells (VSMCs), which were measured by ROS assay, TUNEL staining, and transmission electron microscopy. The result of RNA sequencing of mouse aortas displayed that 232 mRNAs were differently expressed between Ang II and Ang II+CIH groups, and CaMKII-dependent p38/Jnk was confirmed as one downstream signaling of CIH. CaMKII-IN-1, an inhibitor of CaMKII, eliminated the effects of CIH on the loss of primary VSMCs. To conclude, a mouse model of OSA-related AAA, which contains the phenotypes of both AAA and OSA, was established in this study. We suggested CIH as a risk factor of AAA initiation through CaMKII-dependent MAPK signaling.

Epigenetic in Obstructive Sleep Apnea: miR-145-5p targets DNMT3A and regulates DNA methylation homeostasis in upper airway muscle

“…miR-145-5p regulating methylated genes were enriched in the MAPK signaling pathway, which is a major information transmission chain in cell, involved in a series of cell physiological activities such as cell growth, development, differentiation and apoptosis. As it reported that MAPK signaling that chronic intermittent hypoxia regulated the onset and progression of the disease and drug e cacy via the MAPK pathway [30,31], implying that MAPK signaling may be involved in the evolution and development of various diseases under intermittent hypoxia. In addition, enriched pathways such as the cAMP pathway and PI3K/AKT pathway are also reportedly involved in chronic intermittent hypoxia regulating pathophysiological processes in Atherosclerosis and adipocyte metabolism [32,33].…”

Protective effect of Astragaloside IV on chronic intermittent hypoxia-induced vascular endothelial dysfunction through the calpain-1/SIRT1/AMPK signaling pathway

“…The vascular endothelium is formed from a monolayer of endothelial cells that regulate vascular hemostasis, maintains permeability and controls vascular tone. VED is linked with reduced nitric oxide (NO) production or bioavailability and damaged endothelial-dependent vasomotion (Cyr et al, 2020;Xu S. et al, 2021). OSA characterized by intermittent hypoxemia, is a main independent and important risk factor for the occurrence of cardiovascular disease (CVD).…”

“…Early studies showed that VED was associated with calpain overactivation in chronic vascular diseases ( Miyazaki and Miyazaki, 2018 ). Calpain-1 also contributes to oxidative stress, inflammation and adhesiveness to leukocytes ( Xu C. et al, 2021 ). Calpain is involved in the AMPK/eNOS signaling pathway in VED ( Etwebi et al, 2018 ).…”

Impact of obstructive sleep apnea on aortic disease occurrence: A meta-analysis

“…Lastly, contributory role of OSA to AA/AD is still controversial. Although OSA-induced intermittent hypoxia (IH), one of the main features of OSA, has been reported to act as a risk factor of AA and AD via the CaMKII-dependent MAPK 40 and ROS-HIF-1α-MMPs-associated pathways 41 , respectively, another study showed that IH inhibited inflammation and ECM degradation related genes, and alleviated thoracic AD in mice 42 . Therefore, these inconsistences require further investigation.…”