Impact of Short-Term (+)-JQ1 Exposure on Mouse Aorta: Unanticipated Inhibition of Smooth Muscle Contractility

Author:

Yan Binjie12,Gui Yu1,Guo Yanan1,Sun Jiaxing1,Saifeddine Mahmoud3,Deng Jingti1,Hill Joseph A.4,Hollenberg Morley D.3ORCID,Jiang Zhi-Sheng2,Zheng Xi-Long1ORCID

Affiliation:

1. Departments of Biochemistry & Molecular Biology and Physiology & Pharmacology, Libin Cardiovascular Institute, Cumming School of Medicine, The University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada

2. Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, Hengyang Medical College, University of South China, Hengyang 421001, China

3. Department of Physiology & Pharmacology, Cumming School of Medicine, The University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada

4. Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA

Abstract

(+)-JQ1, a specific chemical inhibitor of bromodomain and extraterminal (BET) family protein 4 (BRD4), has been reported to inhibit smooth muscle cell (SMC) proliferation and mouse neointima formation via BRD4 regulation and modulate endothelial nitric oxide synthase (eNOS) activity. This study aimed to investigate the effects of (+)-JQ1 on smooth muscle contractility and the underlying mechanisms. Using wire myography, we discovered that (+)-JQ1 inhibited contractile responses in mouse aortas with or without functional endothelium, reducing myosin light chain 20 (LC20) phosphorylation and relying on extracellular Ca2+. In mouse aortas lacking functional endothelium, BRD4 knockout did not alter the inhibition of contractile responses by (+)-JQ1. In primary cultured SMCs, (+)-JQ1 inhibited Ca2+ influx. In aortas with intact endothelium, (+)-JQ1 inhibition of contractile responses was reversed by NOS inhibition (L-NAME) or guanylyl cyclase inhibition (ODQ) and by blocking the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. In cultured human umbilical vein endothelial cells (HUVECs), (+)-JQ1 rapidly activated AKT and eNOS, which was reversed by PI3K or ATK inhibition. Intraperitoneal injection of (+)-JQ1 reduced mouse systolic blood pressure, an effect blocked by co-treatment with L-NAME. Interestingly, (+)-JQ1 inhibition of aortic contractility and its activation of eNOS and AKT were mimicked by the (−)-JQ1 enantiomer, which is structurally incapable of inhibiting BET bromodomains. In summary, our data suggest that (+)-JQ1 directly inhibits smooth muscle contractility and indirectly activates the PI3K/AKT/eNOS cascade in endothelial cells; however, these effects appear unrelated to BET inhibition. We conclude that (+)-JQ1 exhibits an off-target effect on vascular contractility.

Funder

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada

CSC Studentship

Songlin scholarship at the University of South China

Publisher

MDPI AG

Subject

General Medicine

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