Roles of inflammation in hypertensive organ damages

炎症在高血压器官损伤中的作用

• 批准号: 17590768
• 负责人: KAI Hisashi
• 金额: $ 1.92万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590768/
• 关键词: organ damage; hypertension; heart failure; inflammation; cell, tissue; atherosclerosis

The aim of this study was to determine the role of inflammation in organ damages in chronic hypertension model.(1) Large blood pressure variability-induced aggravation of hypertensive cardiac remodelingWe created a new chronic hypertension model with large blood pressure variability by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHR). Radiotelemetric 24-hour blood pressure monitoring revealed that standard deviation and coefficient of variance of the average of mean blood pressure without changing mean blood pressure in SHR, suggesting that SAD exaggerated blood pressure variability. Seven weeks after SAD or sham operation, the hearts were excised and subjected to the following evaluations. SAD enhanced concentric hypertrophy associated with 1.5-times greater myocyte diameter. Whereas the minimum fibrosis was observed only in the perivascular space in sham+SHR group, SAD+SHR group showed 4-times greater myocardial fibrosis area manifested by ma … More rked perivascular fibrosis and massive, patchy replacement fibrosis. In sham+SHR, only limited number of macrophages were found in the perivascular space. SAD increased the perivascular macrophage infiltration. Real-time RT-PCR analysis demonstrated that SAD induced upregulations of IL-1β, MCP-1, TGF-β, angiotensinogen, angiotensin II type-1 receptor (AT1R) in SHR. When non-depressor dose of candesartan was administered to SAD+SHR, blood pressure variation was not affected. Candesartan prevented the SAD-induced aggravation of myocyte hypertrophy and myocardial fibrosis. The SAD-induced macrophage infiltration and mRNA inductions of MCP-1, TGF-β, angiotensinogen and AT1R were almost abolished in SHR. SAD did not change the circulating levels of catecholamines, angiotensin II and active rennin. Accordingly, it is suggested that large blood pressure variability aggravates hypertensive cardiac remodeling by activating myocardial inflammation. And, the tissue angiotensin system plays a key role in the inflammatory changes induced by large blood pressure variability.(2) Role of inflammatory changes in vascular remodelingInterferon-γ is implicated in the trigger of tissue inflammation, including atherosclerosis. We investigated the effect of interferon-γ function blocking on the atherosclerotic plaques in apoE-/-mice by overexpressing the soluble interferon-γ receptor (sIFNgR) in the thigh muscle as means to make the secreted sIFNgR into the circulation to block the binding of interferon-γ to the receptors on the target cells in remote organs. sIFNgR treatment not only regressed but also stabilized the advanced plaque by reducing the lipid and macrophage accumulations and by increasing the fibrotic tissue smooth muscle cell areas. Thus, interferon-γ-mediated inflammation may be a new therapeutic target of atherosclerosis. Less

本研究的目的是确定炎症在慢性高血压模型器官损害中的作用。(1)大血压变异性导致高血压心脏重构加重我们采用自发性高血压大鼠（SHR）双侧去窦弓神经（SAD）建立了一种新的大血压变异性慢性高血压模型。24小时血压监测结果显示，SAD组平均血压均值的标准差和变异系数均增大，而平均血压无明显变化，提示SAD加重了血压的变异性。SAD或假手术后7周，切除心脏并进行以下评价。SAD增强向心性肥大与1.5倍大的肌细胞直径相关。然而，在sham+SHR组中仅在血管周围空间观察到最小的纤维化，SAD+SHR组显示出4倍于sham + SHR组的心肌纤维化面积，表现为心肌纤维化面积增加。 ...更多信息 rked血管周围纤维化and massive大规模，patched斑片状replacement替代fibrosis纤维化.在sham+SHR中，仅在血管周围间隙中发现有限数量的巨噬细胞。SAD增加血管周围巨噬细胞浸润。实时荧光定量RT-PCR结果显示SAD可诱导SHR细胞内IL-1β、MCP-1、TGF-β、血管紧张素原、血管紧张素Ⅱ 1型受体（AT 1 R）表达上调。当给予SAD+SHR非降压剂量的坎地沙坦时，血压变化不受影响。坎地沙坦可预防SAD诱导的心肌细胞肥大和心肌纤维化的加重。SAD诱导的SHR巨噬细胞浸润及MCP-1、TGF-β、血管紧张素原和AT 1 R mRNA的诱导几乎被消除。SAD没有改变循环中的儿茶酚胺、血管紧张素II和活性凝乳酶水平。因此，这表明，大的血压变异性加剧高血压心脏重构通过激活心肌炎症。并且，组织血管紧张素系统在血压大波动性引起的炎症变化中起关键作用。(2)炎症变化在血管重塑中的作用干扰素-γ与组织炎症的触发有关，包括动脉粥样硬化。我们研究了干扰素-γ功能阻断对apoE-/-小鼠动脉粥样硬化斑块的影响，方法是在大腿肌肉中过表达可溶性干扰素-γ受体（sIFNgR），使分泌的sIFNgR进入循环，阻断干扰素-γ与远端器官靶细胞上的受体结合。sIFNgR治疗不仅使晚期斑块消退，而且通过减少脂质和巨噬细胞积聚以及通过增加纤维化组织平滑肌细胞面积来稳定晚期斑块。因此，干扰素-γ介导的炎症反应可能成为动脉粥样硬化治疗的新靶点。少

项目成果

Pressure overload-induced oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II.

压力超负荷诱导的氧化应激通过血管紧张素 II 介导血管周围炎症和心脏纤维化。

• 发表时间: 2006
• 期刊: Hypertens Res 29 (9)
• 作者: Hosseinkhani M;Hasegawa K;et al.;小野克重;Kai H(他11名1番目)
• 通讯作者: Kai H(他11名1番目)

Postnatal blocking of interferon-g function prevented atherosclerotic plaque formation in apolipoprotein E-knockout mice.

出生后阻断干扰素-g 功能可防止载脂蛋白 E 敲除小鼠中动脉粥样硬化斑块的形成。

• 发表时间: 2007
• 期刊: Hypertens Res 30
• 作者: Koga M;Kai H;Yasukawa H;Kato S;Yamamoto T;Kawai Y;Kusaba K;Seki Y;Kai M;Egashira K;Kataoka Y;Imaizumi T
• 通讯作者: Imaizumi T

Characteristic features of QRST integral mapping in patients with high-risk Brugada syndrome.

高危 Brugada 综合征患者 QRST 积分映射的特征。

• 发表时间: 2007
• 期刊: Circ J 71(1)
• 作者: Kanahara M;Kai H(他5名2番目)
• 通讯作者: Kai H(他5名2番目)

Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is strongly associated with the metabolic syndrome.

通过[18F]-氟脱氧葡萄糖正电子发射断层扫描评估的血管炎症与代谢综合征密切相关。

• 发表时间: 2007
• 期刊: J Am Coll Cardiol 49(14)
• 作者: Tahara N;Kai H;Yamagishi S;Mizoguchi M;Nakaura H;Ishibashi M;Kaida H;Baba K;Hayabuchi N;Imaizumi T
• 通讯作者: Imaizumi T

"Lead-tube" like aorta with intractable systolic hypertension

“导联管”状主动脉伴顽固性收缩期高血压

• 发表时间: 2005
• 期刊: Clin Cardiol 28(9)
• 作者: Kai H;(他2名;1番目)
• 通讯作者: 1番目)