Roles of inflammation in hypertensive organ damages

本研究旨在探讨炎症在慢性高血压模型脏器损伤中的作用。(1)血压大变异性加重高血压心脏重构我们通过对自发性高血压大鼠（SHR）行双侧窦主动脉去神经支配术（SAD），建立了血压大变异性的慢性高血压模型。24小时无线遥测血压监测显示，SHR患者平均血压平均值的标准差和方差系数没有改变平均血压，表明SAD夸大了血压变异性。在SAD或假手术后7周，将心脏切除并进行以下评估。SAD增强同心圆肥大，心肌细胞直径增大1.5倍。sham+SHR组仅在血管周围可见最小的纤维化，而SAD+SHR组的心肌纤维化面积增加了4倍，表现为血管周围纤维化和大量斑块性替代纤维化。在sham+SHR中，血管周围只发现少量巨噬细胞。SAD增加血管周围巨噬细胞浸润。Real-time RT-PCR分析显示，SAD诱导SHR中IL-1β、MCP-1、TGF-β、血管紧张素原、血管紧张素II型1受体（AT1R）表达上调。当给予非降压剂量坎地沙坦时，SAD+SHR的血压变化不受影响。坎地沙坦可预防sad诱导的心肌细胞肥大和心肌纤维化加重。SHR几乎完全消除了sad诱导的巨噬细胞浸润和MCP-1、TGF-β、血管紧张素原和AT1R mRNA诱导。SAD没有改变儿茶酚胺、血管紧张素II和活性肾素的循环水平。因此，我们认为大的血压变异性通过激活心肌炎症加重高血压心脏重构。并且，组织血管紧张素系统在由血压大变异性引起的炎症变化中起关键作用。(2)炎症变化在血管重构中的作用干扰素-γ参与组织炎症的触发，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，通过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受体的结合。通过减少脂质和巨噬细胞积聚以及增加纤维化组织平滑肌细胞面积，sIFNgR治疗不仅可以缓解并稳定晚期斑块。因此，干扰素-γ介导的炎症可能是动脉粥样硬化的一个新的治疗靶点。少

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