ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery
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ORIGINAL ARTICLE
ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery Joon-Tae Kim 1 & So Yeon Won 2 & KyungWook Kang 1 & Sang-Hoon Kim 1 & Man-Seok Park 1 & Kang-Ho Choi 1 & Tai-Seung Nam 1 & Simone W. Denis 3 & Sacha Ferdinandusse 3 & Ji Eun Lee 2 & Seok-Yong Choi 4 & Myeong-Kyu Kim 1 Received: 29 July 2019 / Revised: 30 December 2019 / Accepted: 2 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Recurrent spontaneous vasospasm of the extracranial internal carotid artery (RSV-eICA) is a rarely recognized cause of ischemic stroke in young adults. However, its pathophysiology remains largely unknown. Through whole-exome sequencing of the ACOX3 gene of two dizygotic Korean twin brothers affected by RSV-eICA, we identified two compound heterozygous missense variants c.235 T > G (p.F79 V) and c.665G > A (p.G222E). In silico analysis indicated that both variants were classified as pathogenic. In vitro ACOX3 enzyme assay indicated practically no enzyme activity in both F79 V and G222E mutants. To determine the effect of the mutants on vasospasm, we used a collagen contraction assay on human aortic smooth muscle cells (HASMC). Carbachol, a cholinergic agonist, induces contraction of HASMC. Knockdown of ACOX3 in HASMC, using siRNA, significantly repressed HASMC contraction triggered by carbachol. The carbachol-induced HASMC contraction was restored by transfection with plasmids encoding siRNAresistant wild-type ACOX3, but not by transfection with ACOX3 G222E or by co-transfection with ACOX3 F79 Vand ACOX3 G222E, indicating that the two ACOX3 mutants suppress carbachol-induced HASMC contraction. We propose that an ACOX3 dysfunction elicits a prolonged loss of the basal aortic myogenic tone. As a result, smooth muscles of the ICA’s intermediate segment, in which the sympathetic innervation is especially rich, becomes hypersensitive to sympathomimetic stimuli (e.g., heavy exercise) leading to a recurrent vasospasm. Therefore, ACOX3 dysfunction would be a causal mechanism of RSV-eICA. For the first time, we report the possible involvement of ACOX3 in maintaining the basal myogenic tone of human arterial smooth muscle. Keywords Vasospasm . Internal carotid artery . ACOX3 . Whole exome sequencing . Collagen contraction assay Joon-Tae Kim and So Yeon Won contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-020-00779-z) contains supplementary material, which is available to authorized users. * Ji Eun Lee [email protected] * Seok-Yong Choi [email protected] * Myeong-Kyu Kim [email protected] 1
Department of Neurology, Chonnam National University Medical School, Gwangju 61469, South Korea
2
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, South Korea
3
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands
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