K_Ca3.1 Inhibition Decreases Size and Alters Composition of Atherosclerotic Lesions Induced by Low, Oscillatory Flow

Authors

Darla L. Tharp¹, Douglas K. Bowles^{1, 2, *,}

¹Department of Biomedical Sciences, E102 Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA

²Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA

^*Corresponding author. Email: bowlesd@missouri.edu

DOI

10.2991/artres.k.210202.001How to use a DOI?

Keywords

Kcnn4; REST; NRSF; oscillatory flow; carotid artery; atherosclerosis

Abstract

Low, oscillatory flow/shear patterns are associated with atherosclerotic lesion development. Increased expression of K_Ca3.1 has been found in Vascular Smooth Muscle (VSM), macrophages and T-cells in lesions from humans and mice. Increased expression of K_Ca3.1, is also required for VSM cell proliferation and migration. Previously, we showed that the specific K_Ca3.1 inhibitor, TRAM-34, could inhibit coronary neointimal development following balloon injury in swine. Atherosclerosis develops in regions with a low, oscillatory (i.e. atheroprone) flow pattern. Therefore, we used the Partial Carotid Ligation (PCL) model in high-fat fed, Apoe^−/− mice to determine the role of K_Ca3.1 in atherosclerotic lesion composition and development. PCL was performed on 8–10 week old male Apoe^−/− mice and subsequently placed on a Western diet (TD.88137, Teklad) for 4 weeks. Mice received daily s.c. injections of TRAM-34 (120 mg/kg) or equal volumes of vehicle (peanut oil, PO). 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) treatment reduced lesion size ~50% (p < 0.05). In addition, lesions from TRAM-34 treated mice contained less collagen (6% ± 1% vs. 15% ± 2%; p < 0.05), fibronectin (14% ± 3% vs. 32% ± 3%; p < 0.05) and smooth muscle content (19% ± 2% vs. 29% ± 3%; p < 0.05). Conversely, TRAM-34 had no effect on total cholesterol (1455 vs. 1334 mg/dl, PO and TRAM, resp.) or body weight (29.1 vs. 28.8 g, PO and TRAM, resp.). Medial smooth muscle of atherosclerotic carotids showed diminished RE1-Silencing Transcription Factor (REST)/Neural Restrictive Silencing Factor (NRSF) expression, while REST overexpression in vitro inhibited smooth muscle migration. Together, these data support a downregulation of REST/NRSF and upregulation of K_Ca3.1 in determining smooth muscle and matrix content of atherosclerotic lesions.

Copyright

© 2021 The Authors. Publishing services by Atlantis Press International B.V.

Open Access

This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

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TY  - JOUR
AU  - Darla L. Tharp
AU  - Douglas K. Bowles
PY  - 2021
DA  - 2021/02/13
TI  - KCa3.1 Inhibition Decreases Size and Alters Composition of Atherosclerotic Lesions Induced by Low, Oscillatory Flow
JO  - Artery Research
SP  - 93
EP  - 100
VL  - 27
IS  - 2
SN  - 1876-4401
UR  - https://doi.org/10.2991/artres.k.210202.001
DO  - 10.2991/artres.k.210202.001
ID  - Tharp2021
ER  -