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RhoBTB1 reverses established arterial stiffness in angiotensin II-induced hypertension by promoting actin depolymerization. JCI Insight 2022 05 09;7(9)

Date

04/01/2022

Pubmed ID

35358093

Pubmed Central ID

PMC9090250

DOI

10.1172/jci.insight.158043

Scopus ID

2-s2.0-85129954550

Abstract

Arterial stiffness predicts cardiovascular disease and all-cause mortality, but its treatment remains challenging. Mice treated with angiotensin II (Ang II) develop hypertension, arterial stiffness, vascular dysfunction, and a downregulation of Rho-related BTB domain-containing protein 1 (RhoBTB1) in the vasculature. RhoBTB1 is associated with blood pressure regulation, but its function is poorly understood. We tested the hypothesis that restoring RhoBTB1 can attenuate arterial stiffness, hypertension, and vascular dysfunction in Ang II-treated mice. Genetic complementation of RhoBTB1 in the vasculature was achieved using mice expressing a tamoxifen-inducible, smooth muscle-specific RhoBTB1 transgene. RhoBTB1 restoration efficiently and rapidly alleviated arterial stiffness but not hypertension or vascular dysfunction. Mechanistic studies revealed that RhoBTB1 had no substantial effect on several classical arterial stiffness contributors, such as collagen deposition, elastin content, and vascular smooth muscle remodeling. Instead, Ang II increased actin polymerization in the aorta, which was reversed by RhoBTB1. Changes in the levels of 2 regulators of actin polymerization, cofilin and vasodilator-stimulated phosphoprotein, in response to RhoBTB1 were consistent with an actin depolymerization mechanism. Our study reveals an important function of RhoBTB1, demonstrates its vital role in antagonizing established arterial stiffness, and further supports a functional and mechanistic separation among hypertension, vascular dysfunction, and arterial stiffness.

Author List

Fang S, Wu J, Reho JJ, Lu KT, Brozoski DT, Kumar G, Werthman AM, Silva SD Jr, Muskus Veitia PC, Wackman KK, Mathison AJ, Teng BQ, Lin CW, Quelle FW, Sigmund CD

Authors

Chien-Wei Lin PhD Assistant Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
John J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
Bi Qing Teng Biostatistician I in the Institute for Health and Equity department at Medical College of Wisconsin




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

Actins
Angiotensin II
Animals
Hypertension
Mice
Muscle, Smooth, Vascular
Vascular Remodeling
Vascular Stiffness