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.

Abstract

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.

Keywords: HIF-1α, Hippo; Inflammation; Sleep apnea syndrome; Vascular remodeling; YAP.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blood Pressure
  • Cell Line
  • Disease Models, Animal
  • Hippo Signaling Pathway
  • Humans
  • Hypertension* / etiology
  • Hypertension* / genetics
  • Hypertension* / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Male
  • Myocytes, Smooth Muscle / metabolism
  • Oxidative Stress
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Sleep Apnea Syndromes / complications
  • Sleep Apnea Syndromes / genetics
  • Sleep Apnea Syndromes / metabolism
  • Vascular Remodeling* / genetics
  • YAP-Signaling Proteins* / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • YAP-Signaling Proteins
  • Protein Serine-Threonine Kinases
  • Yap1 protein, rat
  • Hif1a protein, rat
  • Adaptor Proteins, Signal Transducing