DPP-4 阻害薬アナグリプチンはマクロファージの浸潤と活性化を抑制し脳動脈瘤増大を予防する

京都大学0048新制・課程博士博士(医学)甲第20983号医博第4329号新制||医||1027(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 竹内 理, 教授 杉田 昌彦, 教授 湊谷 謙司学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Hemodynamic and Histopathological Changes in the Early Phase of the Development of an Intracranial Aneurysm

Hemodynamic stress and chronic inflammation are closely associated with the pathogenesis of intracranial aneurysms (IAs). However, the hemodynamic and biological mechanisms triggering IA formation remain to be elucidated. To clarify them, computational fluid dynamics (CFD) and histopathological analyses in the early phase of IA development using an experimentally induced IA model in rats were conducted. Histological changes in the early phase of IA development were observed under a scanning electron microscope (SEM) and a transmission electron microscope (TEM). Using data from 7-T magnetic resonance angiography (7T-MRA), CFD analyses were performed to determine wall shear stress (WSS) and wall pressure (WP) at the prospective site of IA. A bump-like protrusion named an “intimal pad” was located in the anterior cerebral artery (ACA) immediately distal to the apex of the bifurcation. TEM showed the degeneration of the internal elastic lamina (IEL) and longitudinally elongated smooth muscle cells (SMCs) that switched from the contractile to the proliferative phenotype and penetrated between two divided layers of the degenerated IEL in the prospective site of the IA. However, no inflammatory cells were observed. CFD analyses showed no particular pattern of WSS and WP at the prospective IA site. IEL degeneration and the phenotypic change and longitudinal elongation of SMCs were identified as the early events in IA development. CFD analyses and TEM data suggest that these biological events may be derived from increased circumferential wall stress due to increased blood pressure and increased longitudinal wall strain due to the existence of the intimal pad

TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

Inflammation is emerging as a critical factor in the pathophysiology of intracranial aneurysm. TLR4 (toll-like receptor 4) contributes not only to the innate immune responses but also to the inflammatory processes associated with vascular disease. Therefore, we examined the contribution of the TLR4 pathway to the development of the rupture of intracranial aneurysm. We used a mouse model of intracranial aneurysm. TLR4 inhibition significantly reduced the development of aneurysmal rupture. In addition, the rupture rate and levels of proinflammatory cytokines were lower in TLR4 knockout mice than the control littermates. Macrophage/monocyte-specific TLR4 knockout mice had a lower rupture rate than the control littermate mice. Moreover, the deficiency of MyD88 (myeloid differentiation primary-response protein 88), a key mediator of TLR4, reduced the rupture rate. These findings suggest that the TLR4 pathway promotes the development of intracranial aneurysmal rupture by accelerating inflammation in aneurysmal walls. Inhibition of the TLR4 pathway in inflammatory cells may be a promising approach for the prevention of aneurysmal rupture and subsequent subarachnoid hemorrhage

Expression of Vasohibin-1 in Human Carotid Atherosclerotic Plaque

[Aim]: In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques. [Methods]: We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls. [Results]: Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r=0.788, p=0.004; r=0.99, p＜0.001; r=0.94, p＜0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque. [Conclusions]: The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke

sj-pdf-1-vmj-10.1177_1358863X231225463 – Supplemental material for Risk factors for recurrent ischemic events in symptomatic carotid artery stenosis on CT angiography

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X231225463 for Risk factors for recurrent ischemic events in symptomatic carotid artery stenosis on CT angiography by Takeyoshi Tsutsui, Kiyofumi Yamada, Taichi Ikedo, Yoshiaki Morita, Eika Hamano, Hirotoshi Imamura, Hisae Mori, Koji Iihara and Hiroharu Kataoka in Vascular Medicine</p

Potential Influences Of Gut Microbiota On The Formation Of Intracranial Aneurysm

Gut microbiota modulates metabolic and immunoregulatory axes and contributes to the pathophysiology of diseases with inflammatory components, such as atherosclerosis, diabetes mellitus, and ischemic stroke. Inflammation is emerging as a critical player in the pathophysiology of an intracranial aneurysm. Therefore, we hypothesized that the gut microbiota affects aneurysm formation by modulating inflammation. We induced intracranial aneurysms in mice by combining systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Depletion of the gut microbiota was achieved via an oral antibiotic cocktail of vancomycin, metronidazole, ampicillin, and neomycin. Antibiotics were given 3 weeks before aneurysm induction and either continued until the end of the experiment or stopped 1 day before aneurysm induction. We also assessed the effects of the gut microbiota depletion on macrophage infiltration and mRNA levels of inflammatory cytokines. Gut microbiota depletion by antibiotics reduced the incidence when antibiotics were started 3 weeks before aneurysm induction and continued until the end of the experiment (83% versus 6%, P\u3c0.001). Even when antibiotics were stopped 1 day before aneurysm induction, the gut microbiota depletion significantly reduced the incidence of aneurysms (86% versus 28%, P\u3c0.05). Both macrophage infiltration and mRNA levels of inflammatory cytokines were reduced with gut microbiota depletion. These findings suggest that the gut microbiota contributes to the pathophysiology of aneurysms by modulating inflammation. Human studies are needed to determine the exact contribution of the gut microbiota to the pathophysiology of aneurysm formation and disease course in humans

The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity

<div><p>With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E₂ suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated <i>db/db</i> mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation <i>in vivo</i>. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined <i>in vitro</i> M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.</p></div