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.
Highlights
Obstructive sleep apnea (OSA) refers to the repeated upper airway obstruction during sleep, which can cause hypopnea and apnea
OSA is highly prevalent in patients with abdominal aortic aneurysm (AAA) [7], and severe OSA may promote the expansion of AAA [8]
chronic intermittent hypoxia (CIH) exposure significantly upregulated the Bax and cleaved caspase-3 expressions while downregulating the Bcl-2 expression (p < 0:05, Figures 3(g) and 3(h)). These results demonstrate that CIH exposure induced reactive oxygen species (ROS) generation and promoted exaggerated vascular smooth muscle cells (VSMCs) apoptosis
Summary
Obstructive sleep apnea (OSA) refers to the repeated upper airway obstruction during sleep, which can cause hypopnea and apnea. The main clinical features of OSA include snoring, frequent awakening, witnessed apneas, recurrent hypoxemia, hypercapnia, and sleep fragmentation, which seriously affect the quality of life of patients with OSA. It has been reported by the Wisconsin Sleep Cohort study that the prevalence of moderate to severe OSA among 30-70 years old adults seems to be 10% [1]. Patients with OSA may be prone to the initiation of AAA since the repeated apnea leads to sympathetic nerve activation, arterial pressure elevation, oxidative stress, and Oxidative Medicine and Cellular Longevity excessive inflammation [8, 10]. The effect of OSA on the initiation of AAA has not been completely studied
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