HIF-1α mediates hypertension and vascular remodeling in sleep apnea via hippo-YAP pathway activation
- Mol Med. 2024 Dec 28;30(1):281. doi: 10.1186/s10020-024-00987-5.
- 1. Department of Otorhinolaryngology/Head and Neck, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No.3 East Qingchun Road, Hangzhou, 310020, Zhejiang, China.
- 2. Department of Otorhinolaryngology/Head and Neck, Aral Hospital, Xinjiang Corps, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Aral, 843399, Xinjiang, China.
- 3. Department of Otorhinolaryngology/Head and Neck, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No.3 East Qingchun Road, Hangzhou, 310020, Zhejiang, China. [email protected].
- 4. Department of Otorhinolaryngology/Head and Neck, The First People's Hospital of Lin'an District, Hangzhou, 311300, Zhejiang, China.
- 5. Department of Nursing, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, Zhejiang, China.
Background: Sleep apnea syndrome (SAS) is associated with Hypertension and vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α) and the Hippo-YAP pathway are implicated in these processes, but their specific roles remain unclear. This study investigated the HIF-1α/Hippo-YAP pathway in SAS-related Hypertension.
Methods: We established a rat model of SAS-induced Hypertension via chronic intermittent hypoxia (CIH). Rats were treated with siRNA targeting HIF-1α. Blood pressure, inflammation, oxidative stress, vascular remodeling, and VSMC function were assessed. In vitro experiments with A7r5 cells and human aortic smooth muscle cells (HAoSMCs) explored the effects of HIF-1α silencing and YAP1 overexpression.
Results: Compared with the control group, the CIH group presented significant increases in both HIF-1α and YAP1 expression, which correlated with increased blood pressure and vascular changes. HIF-1α silencing reduced Hypertension, oxidative stress, inflammation, and the severity of vascular remodeling. Specifically, siRNA treatment for HIF-1α normalized blood pressure, decreased the levels of oxidative damage markers (increased SOD and decreased MDA), and reversed the changes in the levels of inflammatory markers (decreased high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and soluble E-Selectin (sE-s)). Structural analyses revealed reduced vascular smooth muscle cell proliferation and Collagen deposition, along with normalization of cellular markers, such as α-SMA and TGF-β1. Furthermore, the Hippo-YAP pathway appeared to mediate these effects, as evidenced by altered YAP1 expression and activity upon HIF-1α modulation.
Conclusions: Our findings demonstrate the significance of the HIF-1α/Hippo-YAP pathway in CIH-induced Hypertension and vascular remodeling. HIF-1α contributes to these pathophysiological processes by promoting oxidative stress, inflammation, and aberrant VSMC behavior. Targeting this pathway could offer new therapeutic strategies for CIH-related cardiovascular complications in SAS patients.