Faculty Collaboration Database

Endothelial Rap1 (Ras-Association Proximate 1) Restricts Inflammatory Signaling to Protect From the Progression of Atherosclerosis. Arterioscler Thromb Vasc Biol 2021 Feb;41(2):638-650

Date

12/04/2020

Pubmed ID

33267664

Pubmed Central ID

PMC8105264

DOI

10.1161/ATVBAHA.120.315401

Scopus ID

2-s2.0-85104181830 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

OBJECTIVE: Small GTPase Rap1 (Ras-association proximate 1) is a novel, positive regulator of NO release and endothelial function with a potentially key role in mechanosensing of atheroprotective, laminar flow. Our objective was to delineate the role of Rap1 in the progression of atherosclerosis and its specific functions in the presence and absence of laminar flow, to better define its role in endothelial mechanisms contributing to plaque formation and atherogenesis. Approach and Results: In a mouse atherosclerosis model, endothelial Rap1B deletion exacerbates atherosclerotic plaque formation. In the thoracic aorta, where laminar shear stress-induced NO is otherwise atheroprotective, plaque area is increased in Athero-Rap1B^iΔEC (atherogenic endothelial cell-specific, tamoxifen-inducible Rap1A+Rap1B knockout) mice. Endothelial Rap1 deficiency also leads to increased plaque size, leukocyte accumulation, and increased CAM (cell adhesion molecule) expression in atheroprone areas, whereas vascular permeability is unchanged. In endothelial cells, in the absence of protective laminar flow, Rap1 deficiency leads to an increased proinflammatory TNF-α (tumor necrosis factor alpha) signaling and increased NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and elevated inflammatory receptor expression. Interestingly, this increased signaling to NF-κB activation is corrected by AKTVIII-an inhibitor of Akt (protein kinase B) translocation to the membrane. Together, these data implicate Rap1 in restricting Akt-dependent signaling, preventing excessive cytokine receptor signaling and proinflammatory NF-κB activation.

CONCLUSIONS: Via 2 distinct mechanisms, endothelial Rap1 protects from the atherosclerosis progression in the presence and absence of laminar flow; Rap1-stimulated NO release predominates in laminar flow, and restriction of proinflammatory signaling predominates in the absence of laminar flow. Our studies provide novel insights into the mechanisms underlying endothelial homeostasis and reveal the importance of Rap1 signaling in cardiovascular disease.

Author List

Singh B, Kosuru R, Lakshmikanthan S, Sorci-Thomas MG, Zhang DX, Sparapani R, Vasquez-Vivar J, Chrzanowska M

Authors

Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Rodney Sparapani PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Aortic Diseases
Atherosclerosis
Cells, Cultured
Cytokines
Diet, High-Fat
Disease Models, Animal
Disease Progression
Endothelial Cells
Female
Humans
Inflammation
Inflammation Mediators
Leukocytes
Male
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
NF-kappa B
Nitric Oxide
Plaque, Atherosclerotic
Signal Transduction
rap GTP-Binding Proteins
rap1 GTP-Binding Proteins