Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast–like Cells Is Driven by an Unfolded Protein Response

Author:

Chattopadhyay Abhijnan1,Kwartler Callie S.1ORCID,Kaw Kaveeta1ORCID,Li Yanming2ORCID,Kaw Anita1,Chen Jiyuan1,LeMaire Scott A.2ORCID,Shen Ying H.2ORCID,Milewicz Dianna M.1

Affiliation:

1. Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX (A.C., C.S.K., K.K., A.K., J.C., D.M.M.).

2. Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, TX (.L., S.A.L., Y.H.S.).

Abstract

Objective:Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching.Approach and Results:With exposure to free methyl-β-cyclodextrin cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents methyl-β-cyclodextrin cholesterol–induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin, and thapsigargin is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs.Conclusions:Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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