Roles of inflammation in hypertensive organ damages

本研究旨在探讨炎症在慢性高血压模型器官损害中的作用。(1)高血压变异性导致高血压心脏重构加重。本研究采用双侧去窦弓神经(SAD)的方法建立了一种新的高血压模型。无线遥测24小时血压监测显示，SHR平均血压平均值的标准差和变异系数不改变平均血压，提示SAD夸大了血压变异性。SAD或假手术后7周，摘除心脏，进行以下评估。AD强化的向心性肥厚与1.5倍的心肌细胞直径相关。而假手术+自发性高血压组仅在血管周围观察到最小的纤维化，而自发性高血压+自发性高血压组的心肌纤维化面积是…组的4倍。更多的RKED血管周围纤维化和大量、斑片状的替代性纤维化。假手术+自发性高血压大鼠血管周围仅见少量巨噬细胞。SAD组大鼠血管周围巨噬细胞浸润增多。实时定量逆转录聚合酶链式反应显示，自发性高血压大鼠IL-1β、单核细胞趋化蛋白-1、转化生长因子-β、血管紧张素原、血管紧张素Ⅱ1型受体(AT1R)表达上调。非降压剂量坎地沙坦对SAD+SHR的血压变化无影响。坎地沙坦可预防SAD所致的心肌细胞肥大和心肌纤维化的加重。自发性高血压大鼠单核细胞趋化蛋白-1、转化生长因子-β、血管紧张素原、血管紧张素原和血管紧张素Ⅱ受体的表达几乎完全消失。SAD不改变循环中儿茶酚胺、血管紧张素II和活性肾素的水平。因此，我们认为，大的血压变异性通过激活心肌炎症而加重高血压心脏重构。组织血管紧张素系统在大血压变异性引起的炎症改变中起关键作用。(2)炎症改变在血管重构中的作用干扰素-γ参与了包括动脉粥样硬化在内的组织炎症的触发。我们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进入血液循环，阻断干扰素-γ与远隔器官靶细胞上受体的结合，研究了干扰素-γ功能阻断对载脂蛋白E-/-小鼠动脉粥样硬化斑块的影响。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的积聚，增加纤维化组织的平滑肌细胞面积而稳定斑块。因此，干扰素-γ介导的炎症可能成为动脉粥样硬化治疗的新靶点。较少

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