Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Cristina M. Ramírez
  • Xinbo Zhang
  • Chirosree Bandyopadhyay
  • Noemi Rotllan
  • Michael G. Sugiyama
  • Binod Aryal
  • Xinran Liu
  • Shun He
  • Jan R. Kraehling
  • Victoria Ulrich
  • Chin Sheng Lin
  • Heino Velazquez
  • Miguel A. Lasunción
  • Guangxin Li
  • Yajaira Suárez
  • George Tellides
  • Filip K. Swirski
  • Warren L. Lee
  • William C. Sessa
  • Carlos Fernández-Hernando

Abstract

BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear. METHODS: Triple-knockout mouse lacking expression of eNOS, Cav1, and Ldlr were generated to explore the role of NO production in Cav1-dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. RESULTS: We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr-/-eNOS-/- mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flow-dependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. CONCLUSIONS: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.

Bibliographical metadata

Original languageEnglish
Pages (from-to)225-239
Number of pages15
JournalCirculation
Volume140
Issue number3
Early online date3 Jun 2019
DOIs
Publication statusPublished - 16 Jul 2019