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

AbstractRecurrent 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 aor tic smooth muscle cells (HASMC). Carbachol, a cholinergic agonist, induces contraction of HASMC. Knockdown ofACOX3 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-typeACOX3, but not by transfection withACOX3 G222E or by co-transfection withACOX3 F79  V andACOX3 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 sympathomimet...
Source: Translational Stroke Research - Category: Neurology Source Type: research