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Endothelial PHACTR1 Promotes Endothelial Activation and Atherosclerosis by Repressing PPARγ Activity Under Disturbed

Dongyang Jiang1, Hao Liu1, Guofu Zhu1

  • 1Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (D.J., H.L., G.Z., X.L., L.F., F.Z., C.X., Z.Y., Y.Y., J.G., Y.X.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|May 18, 2023
PubMed

Insights

Endothelial PHACTR1 promotes atherosclerosis by acting as a PPARγ corepressor in disturbed flow regions. Targeting endothelial PHACTR1 offers a potential therapeutic strategy for treating coronary artery disease.

Area of Science:

  • Cardiovascular Biology
  • Molecular Mechanisms of Atherosclerosis

Background:

  • Single nucleotide polymorphisms (SNPs) at the PHACTR1 locus are strongly associated with coronary artery disease (CAD).
  • The precise biological role of PHACTR1 in cardiovascular disease, particularly in endothelial cells, remains largely uncharacterized.
  • This study investigates the contrasting roles of PHACTR1 in macrophages versus endothelial cells (ECs) in the context of atherosclerosis.

Purpose of the Study:

  • To elucidate the function of PHACTR1 in endothelial cells (ECs) and its contribution to atherosclerosis.
  • To identify the molecular pathways regulated by endothelial PHACTR1.
  • To evaluate endothelial PHACTR1 as a potential therapeutic target for atherosclerosis.

Main Methods:

  • Generated global and EC-specific PHACTR1 knockout (KO) mice, crossed with Apoe-deficient mice.
  • Induced atherosclerosis using high-fat/high-cholesterol diet and partial carotid artery ligation.
  • Investigated PHACTR1 localization, molecular function via RNA sequencing, and endothelial activation in vitro and in vivo.

Main Results:

  • EC-specific PHACTR1 deficiency significantly reduced atherosclerosis in disturbed flow regions.
  • PHACTR1 acts as a transcriptional corepressor for PPARγ, binding to it via corepressor motifs.
  • PHACTR1 deficiency inhibited endothelial activation, a key process in atherosclerosis development, particularly under disturbed flow conditions.
  • PPARγ activation is protective against atherosclerosis by suppressing endothelial activation, and its inhibition by PHACTR1 promotes disease.

Conclusions:

  • Endothelial PHACTR1 functions as a novel PPARγ corepressor, promoting atherosclerosis in disturbed flow areas.
  • Targeting endothelial PHACTR1 represents a promising therapeutic strategy for atherosclerosis treatment.
Abstract

Keywords:
PPAR gammaatherosclerosisblood flowendothelial cellsinflammation

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