Abstract
BackgroundAs subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health.MethodsUsing previously obtained gene expression profile data from surgically resected unruptured human IA lesions, we selected G-protein coupled receptor 120 (GPR120) as a gene whose expression is significantly higher in lesions than that in control arterial walls. To corroborate a contribution of GPR120 signaling to the pathophysiology, we used an animal model of IAs and examine the effect of a GPR120 agonist on the progression of the disease. IA lesion was induced in rats through an increase of hemodynamic stress achieved by a one-sided carotid ligation and induced hypervolemia. Eicosapentaenoic acid (EPA) was used as an agonist for GPR120 in this study and its effect on the size of IAs, the thinning of media, and infiltration of macrophages in lesions were examined.ResultEPA administered significantly suppressed the size of IAs and the degenerative changes in the media in rats. EPA treatment also inhibited infiltration of macrophages, a hallmark of inflammatory responses in lesions. In in vitro experiments using RAW264.7 cells, pre-treatment of EPA partially suppressed lipopolysaccharide-induced activation of nuclear factor-kappa B and also the transcriptional induction of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant for macrophages to accumulate in lesions. As a selective agonist of GPR120, TUG-891, could reproduce the effect of EPA in RAW264.7 cells, EPA presumably acted on this receptor to suppress inflammatory responses. Consistently, EPA remarkably suppressed MCP-1 expression in lesions, suggesting the in vivo relevance of in vitro studies.ConclusionsThese results combined together suggest the potential of the medical therapy targeting GPR120 or using EPA to prevent the progression of IAs.
Highlights
As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health
Over-expression of G-protein coupled receptor 120 (GPR120) in human IA walls revealed by RNA sequencing analysis and protein expression of GPR120 in human IA lesions We picked up GPR120 (free fatty acid receptor 4 (FFAR4)) as a putative therapeutic target from G-protein coupled receptors (GPCRs) whose expression was significantly upregulated in human unruptured IA lesions (n = 4) compared with those in control arterial walls (n = 3) (p = 7.95E−10) from previously obtained comprehensive gene expression profile data by RNA-sequencing analysis [10] (ID number #PRJNA553307 at BioProject database)
Other positive signals for GPR120 staining observed in IA walls were colocalized with the marker of macrophages, CD68, in Effect of a ligand of GPR120, Eicosapentaenoic acid (EPA), on the progression of IAs induced in a rat model We selected EPA as an agonist for GPR120 [11, 19] because EPA is the already-approved drug for a clinical usage
Summary
As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health. Subarachnoid hemorrhage (SAH) mainly caused by the rupture of an intracranial aneurysm (IA) has the mortality rate as high as 50% within 1 month from the onset [1, 2], making this disease being one of the most serious health problems. Because the prevalence of unruptured IAs in general population is high, 2–4% [5], and IA can cause the lethal SAH after rupture, the preemptive treatment of unruptured IAs to prevent the onset of SAH is mandatory for social health. The establishment of less-invasive medical treatment to prevent the progression and the rupture of IAs is a matter to be urgently addressed
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