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Published in: Translational Stroke Research 5/2020

01-10-2020 | Original Article

ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery

Authors: Joon-Tae Kim, So Yeon Won, KyungWook Kang, Sang-Hoon Kim, Man-Seok Park, Kang-Ho Choi, Tai-Seung Nam, Simone W. Denis, Sacha Ferdinandusse, Ji Eun Lee, Seok-Yong Choi, Myeong-Kyu Kim

Published in: Translational Stroke Research | Issue 5/2020

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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 siRNA-resistant wild-type ACOX3, but not by transfection with ACOX3 G222E or by co-transfection with ACOX3 F79 V and 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.
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Literature
1.
go back to reference Arning C, Schrattenholzer A, Lachenmayer L. Cervical carotid artery vasospasms causing cerebral ischemia: detection by immediate vascular ultrasonographic investigation. Stroke. 1998;29:1063–6.CrossRef Arning C, Schrattenholzer A, Lachenmayer L. Cervical carotid artery vasospasms causing cerebral ischemia: detection by immediate vascular ultrasonographic investigation. Stroke. 1998;29:1063–6.CrossRef
2.
go back to reference Janzarik WG, Ringleb PA, Reinhard M, Rauer S. Recurrent extracranial carotid artery vasospasms: report of 2 cases. Stroke. 2006;37:2170–3.CrossRef Janzarik WG, Ringleb PA, Reinhard M, Rauer S. Recurrent extracranial carotid artery vasospasms: report of 2 cases. Stroke. 2006;37:2170–3.CrossRef
3.
go back to reference Yoshimoto H, Matsuo S, Umemoto T, Kawakami N, Moriyama T. Idiopathic carotid and coronary vasospasm: a new syndrome? J Neuroimaging. 2011;21:273–6.CrossRef Yoshimoto H, Matsuo S, Umemoto T, Kawakami N, Moriyama T. Idiopathic carotid and coronary vasospasm: a new syndrome? J Neuroimaging. 2011;21:273–6.CrossRef
4.
go back to reference Solomon S, Lipton RB, Harris PY. Arterial stenosis in migraine: spasm or arteriopathy? Headache. 1990;30:52–61.CrossRef Solomon S, Lipton RB, Harris PY. Arterial stenosis in migraine: spasm or arteriopathy? Headache. 1990;30:52–61.CrossRef
5.
go back to reference Magnin E, Mouton S, Abouaf L, Dumas-Stoeckel S, Hermier M, Tilikete C, et al. Idiopathic vasospastic angiopathy of the internal carotid arteries: a rarely recognized cause of ischemic stroke in young individuals. Rev Neurol. (Paris) 2011;167:626-631. Magnin E, Mouton S, Abouaf L, Dumas-Stoeckel S, Hermier M, Tilikete C, et al. Idiopathic vasospastic angiopathy of the internal carotid arteries: a rarely recognized cause of ischemic stroke in young individuals. Rev Neurol. (Paris) 2011;167:626-631.
6.
go back to reference Yokoyama H, Yoneda M, Abe M, Sakai T, Sagoh T, Adachi Y, et al. Internal carotid artery vasospasm syndrome: demonstration by neuroimaging. J Neurol Neurosurg Psychiatry. 2006;77:888–9.CrossRef Yokoyama H, Yoneda M, Abe M, Sakai T, Sagoh T, Adachi Y, et al. Internal carotid artery vasospasm syndrome: demonstration by neuroimaging. J Neurol Neurosurg Psychiatry. 2006;77:888–9.CrossRef
7.
go back to reference Kuzumoto Y, Mitsui Y, Ueda H, Kusunoki S. Vasospastic cerebral infarction induced by smoking: a case report. No To Shinkei. 2005;57:33–6.PubMed Kuzumoto Y, Mitsui Y, Ueda H, Kusunoki S. Vasospastic cerebral infarction induced by smoking: a case report. No To Shinkei. 2005;57:33–6.PubMed
8.
go back to reference Moeller S, Hilz MJ, Blinzler C, Koehn J, Doerfler A, Schwab S, et al. Extracranial internal carotid artery vasospasm due to sympathetic dysfunction. Neurology. 2012;78:1892–4.CrossRef Moeller S, Hilz MJ, Blinzler C, Koehn J, Doerfler A, Schwab S, et al. Extracranial internal carotid artery vasospasm due to sympathetic dysfunction. Neurology. 2012;78:1892–4.CrossRef
9.
go back to reference Dembo T, Tanahashi N. Recurring extracranial internal carotid artery vasospasm detected by intravascular ultrasound. Intern Med. 2012;51:1249–53.CrossRef Dembo T, Tanahashi N. Recurring extracranial internal carotid artery vasospasm detected by intravascular ultrasound. Intern Med. 2012;51:1249–53.CrossRef
10.
go back to reference Wopking S, Kastrup A, Lentsching M, Brunner F. Recurrent strokes due to transient vasospasms of the extracranial internal carotid artery. Case Rep Neurol. 2013;5:143–8.CrossRef Wopking S, Kastrup A, Lentsching M, Brunner F. Recurrent strokes due to transient vasospasms of the extracranial internal carotid artery. Case Rep Neurol. 2013;5:143–8.CrossRef
11.
go back to reference Dorsch N. A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl. 2011;110:5–6.PubMed Dorsch N. A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl. 2011;110:5–6.PubMed
12.
go back to reference Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: current and future perspectives. Expert Rev Neurother. 2011;11:1265–76.CrossRef Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: current and future perspectives. Expert Rev Neurother. 2011;11:1265–76.CrossRef
13.
go back to reference Sanin LC, Mathew NT. Severe diffuse intracranial vasospasm as a cause of extensive migrainous cerebral infarction. Cephalalgia. 1993;13:289–92.CrossRef Sanin LC, Mathew NT. Severe diffuse intracranial vasospasm as a cause of extensive migrainous cerebral infarction. Cephalalgia. 1993;13:289–92.CrossRef
14.
go back to reference Smith PG, Killeen TE. Carotid artery vasospasm complicating extensive skull base surgery: cause, prevention, and management. Otolaryngol Head Neck Surg. 1987;97:1–7.CrossRef Smith PG, Killeen TE. Carotid artery vasospasm complicating extensive skull base surgery: cause, prevention, and management. Otolaryngol Head Neck Surg. 1987;97:1–7.CrossRef
15.
go back to reference Senter HJ, Lieverman AN, Pinto R. Cerebral manifestations of ergotism. Report of a case and review of the literature. Stroke. 1976;7:88–92.CrossRef Senter HJ, Lieverman AN, Pinto R. Cerebral manifestations of ergotism. Report of a case and review of the literature. Stroke. 1976;7:88–92.CrossRef
16.
go back to reference Tsuru H, Tanimitsu N, Hirai T. Role of perivascular sympathetic nerves and regional differences in the features of sympathetic innervation of the vascular system. Jpn J Pharmacol. 2002;88:9–13.CrossRef Tsuru H, Tanimitsu N, Hirai T. Role of perivascular sympathetic nerves and regional differences in the features of sympathetic innervation of the vascular system. Jpn J Pharmacol. 2002;88:9–13.CrossRef
17.
go back to reference Ku C-S, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R. Exome sequencing: Dual role as a discovery and diagnostic tool. Ann Neurol. 2012;71:5–14.CrossRef Ku C-S, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R. Exome sequencing: Dual role as a discovery and diagnostic tool. Ann Neurol. 2012;71:5–14.CrossRef
18.
go back to reference Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRef Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRef
19.
go back to reference Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research. 2019;47(DI):D607–13.CrossRef Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research. 2019;47(DI):D607–13.CrossRef
20.
go back to reference Shin DH, Oganesyan N, Jancarik J, Yokota H, Kim R, Kim SH. Crystal structure of a nicotinate phosphoribosyltransferase from Thermoplasma acidophilum. J Biol Chem. 2005;280:18326–35.CrossRef Shin DH, Oganesyan N, Jancarik J, Yokota H, Kim R, Kim SH. Crystal structure of a nicotinate phosphoribosyltransferase from Thermoplasma acidophilum. J Biol Chem. 2005;280:18326–35.CrossRef
21.
go back to reference Aslanidis C, de Jong PJ. Ligation-independent cloning of PCR products (LIC-PCR). Nucleic Acids Res. 1990;18:6069–74.CrossRef Aslanidis C, de Jong PJ. Ligation-independent cloning of PCR products (LIC-PCR). Nucleic Acids Res. 1990;18:6069–74.CrossRef
22.
go back to reference Ferdinandusse S, Denis S, van Roermund CWT, Preece MA, Koster J, Ebberink MS, et al. A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. Biochim Biophys Acta Mol Basis Dis. 1864;2018:952–8. Ferdinandusse S, Denis S, van Roermund CWT, Preece MA, Koster J, Ebberink MS, et al. A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. Biochim Biophys Acta Mol Basis Dis. 1864;2018:952–8.
23.
go back to reference Lee JH, Oh CW, Lee SH, Han DH. Aplasia of the internal carotid artery. Acta Neurochir. 2003;145:117–25.CrossRef Lee JH, Oh CW, Lee SH, Han DH. Aplasia of the internal carotid artery. Acta Neurochir. 2003;145:117–25.CrossRef
24.
go back to reference Monte MJ, Alonso-Peña M, Briz O, Herraez E, Berasain C, Argemi J, et al. ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia. J Hepatol. 2017;66:581–8.CrossRef Monte MJ, Alonso-Peña M, Briz O, Herraez E, Berasain C, Argemi J, et al. ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia. J Hepatol. 2017;66:581–8.CrossRef
25.
go back to reference Vilarinho S, Sari S, Mazzacuva F, Bilgüvar K, Esendagli-Yilmaz G, Jain D, et al. ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment. Proc Natl Acad Sci USA. 2016;113:11289–93.CrossRef Vilarinho S, Sari S, Mazzacuva F, Bilgüvar K, Esendagli-Yilmaz G, Jain D, et al. ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment. Proc Natl Acad Sci USA. 2016;113:11289–93.CrossRef
26.
go back to reference Fournier B, Saudubray JM, Benichou B, Lyonnet S, Munnich A, Clevers H, et al. Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy. J Clin Invest. 1994;94:526–31.CrossRef Fournier B, Saudubray JM, Benichou B, Lyonnet S, Munnich A, Clevers H, et al. Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy. J Clin Invest. 1994;94:526–31.CrossRef
27.
go back to reference Dirkx R, Vanhorebeek I, Martens K, Schad A, Grabenbauer M, Fahimi D, et al. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology. 2005;41:868–78.CrossRef Dirkx R, Vanhorebeek I, Martens K, Schad A, Grabenbauer M, Fahimi D, et al. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology. 2005;41:868–78.CrossRef
28.
go back to reference Sarnat HB, Machin G, Darwish HZ, Rubin SZ. Mitochondrial myopathy of cerebro-hepato-renal (Zellweger) syndrome. Can J Neurol Sci. 1983;10:170–7.CrossRef Sarnat HB, Machin G, Darwish HZ, Rubin SZ. Mitochondrial myopathy of cerebro-hepato-renal (Zellweger) syndrome. Can J Neurol Sci. 1983;10:170–7.CrossRef
29.
go back to reference Wolff J, Nyhan WL, Powell H, Takahashi D, Hutzler J, Hajra AK, et al. Myopathy in an infant with a fatal peroxisomal disorder. Pediatr Neurol. 1986;2:141–6.CrossRef Wolff J, Nyhan WL, Powell H, Takahashi D, Hutzler J, Hajra AK, et al. Myopathy in an infant with a fatal peroxisomal disorder. Pediatr Neurol. 1986;2:141–6.CrossRef
30.
go back to reference Faust JE, Manisundaram A, Ivanova PT, Milne SB, Summerville JB, Brown HA, et al. Peroxisomes are required for lipid metabolism and muscle function in Drosophila melanogaster. PLoS One. 2014;9:e100213.CrossRef Faust JE, Manisundaram A, Ivanova PT, Milne SB, Summerville JB, Brown HA, et al. Peroxisomes are required for lipid metabolism and muscle function in Drosophila melanogaster. PLoS One. 2014;9:e100213.CrossRef
32.
go back to reference Kontos HA, Wei EP, Raper AJ, Rosenblum WI, Navari RM, Patterson JL Jr. Role of tissue hypoxia in local regulation of cerebral microcirculation. Am J Physiol. 1978;234:H582–91.PubMed Kontos HA, Wei EP, Raper AJ, Rosenblum WI, Navari RM, Patterson JL Jr. Role of tissue hypoxia in local regulation of cerebral microcirculation. Am J Physiol. 1978;234:H582–91.PubMed
33.
go back to reference Mellander S. Functional aspects of myogenic vascular control. J Hypertens. 1989;7(Suppl 4):S21–30. Mellander S. Functional aspects of myogenic vascular control. J Hypertens. 1989;7(Suppl 4):S21–30.
34.
go back to reference Osol G, Brekke JF, McElroy-Yaggy K, Gokina NI. Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behavior. Am J Physiol Heart Circ Physiol. 2002;283:H2260–7.CrossRef Osol G, Brekke JF, McElroy-Yaggy K, Gokina NI. Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behavior. Am J Physiol Heart Circ Physiol. 2002;283:H2260–7.CrossRef
35.
go back to reference Cipolla MJ, Osol G. Vascular smooth muscle actin cytoskeleton in cerebral artery forced dilatation. Stroke. 1998;29:1223–8.CrossRef Cipolla MJ, Osol G. Vascular smooth muscle actin cytoskeleton in cerebral artery forced dilatation. Stroke. 1998;29:1223–8.CrossRef
36.
go back to reference Busija DW, Heistad DD. Factors involved in the physiological regulation of the cerebral circulation. Rev Physiol Biochem Pharamacol. 1984;101:161–211.CrossRef Busija DW, Heistad DD. Factors involved in the physiological regulation of the cerebral circulation. Rev Physiol Biochem Pharamacol. 1984;101:161–211.CrossRef
37.
go back to reference Carmicheal P, Lieben J. Sudden death in explosive workers. Arch Environ Health. 1963;14:50–65. Carmicheal P, Lieben J. Sudden death in explosive workers. Arch Environ Health. 1963;14:50–65.
38.
go back to reference Munzel T, Bassenge E. Long-term Angiotensin-Converting Enzyme Inhibition With High-Dose Enalapril Retards Nitrate Tolerance in Large Epicardial Arteries and Prevents Rebound Coronary Vasoconstriction In Vivo. Circulation. 1996;93:2052–8.CrossRef Munzel T, Bassenge E. Long-term Angiotensin-Converting Enzyme Inhibition With High-Dose Enalapril Retards Nitrate Tolerance in Large Epicardial Arteries and Prevents Rebound Coronary Vasoconstriction In Vivo. Circulation. 1996;93:2052–8.CrossRef
39.
go back to reference Idel S, Ellinghaus P, Wolfrum C, Nofer JR, Gloerich J, Assmann G, et al. Branched Chain Fatty Acids Induce Nitric Oxide-dependent Apoptosis in Vascular Smooth Muscle Cells. J Biol Chem. 2002;277:49319–25.CrossRef Idel S, Ellinghaus P, Wolfrum C, Nofer JR, Gloerich J, Assmann G, et al. Branched Chain Fatty Acids Induce Nitric Oxide-dependent Apoptosis in Vascular Smooth Muscle Cells. J Biol Chem. 2002;277:49319–25.CrossRef
40.
go back to reference Young JB, Landsberg L. Diet-induced changes in sympathetic nervous system activity: possible implications for obesity and hypertension. J Chronic Dis. 1982;35:879–86.CrossRef Young JB, Landsberg L. Diet-induced changes in sympathetic nervous system activity: possible implications for obesity and hypertension. J Chronic Dis. 1982;35:879–86.CrossRef
Metadata
Title
ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery
Authors
Joon-Tae Kim
So Yeon Won
KyungWook Kang
Sang-Hoon Kim
Man-Seok Park
Kang-Ho Choi
Tai-Seung Nam
Simone W. Denis
Sacha Ferdinandusse
Ji Eun Lee
Seok-Yong Choi
Myeong-Kyu Kim
Publication date
01-10-2020
Publisher
Springer US
Published in
Translational Stroke Research / Issue 5/2020
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-020-00779-z

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