Hypertensive myocardial fibrosis and Diastolic dysfunction - Another model of inflammation?
Hypertensive myocardial fibrosis and Diastolic dysfunction - Another model of inflammation?
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DOI：
10.1161/01.hyp.0000118584.33350.7d
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发表时间：
2004-04-01
期刊：
影响因子：
8.3
通讯作者：
Imaizumi, T
中科院分区：
文献类型：
--
作者：
Kuwahara, F;Kai, H;Imaizumi, T
过度的心肌纤维化会恶化高血压心脏的舒张功能。表明巨噬细胞参与各种疾病情况的纤维化过程。我们试图研究巨噬细胞在压力超负荷心脏的心肌重塑和心功能障碍中的作用。在肾上主动脉缩窄的 Wistar 大鼠中，压力超负荷诱导血管周围巨噬细胞积聚和成纤维细胞增殖，在第 3 天达到峰值，到第 28 天降至较低水平。肌细胞趋化蛋白 (MCP)-1 mRNA 在第 1 天后上调，在第 3 天达到峰值，到第 28 天恢复到微不足道的水平，而在第 3 天后观察到转化生长因子 (TGF)-β 诱导，在第 28 天达到峰值7 天，并在第 28 天保持相对升高。第 7 天后，出现同心左心室 (LV) 肥大，与反应性纤维化和肌细胞肥大相关。第28天，超声心动图显示左心室缩短分数正常，但二尖瓣多普勒速度早期充盈波与晚期充盈波的比率降低，血流动力学研究显示左心室舒张末压升高，表明收缩功能正常但舒张功能受损。使用抗MCP-1单克隆中和抗体进行长期治疗不仅可以抑制巨噬细胞的积累，还可以抑制成纤维细胞的增殖和TGF-β的诱导。此外，中和抗体减轻心肌纤维化，但不减轻心肌细胞肥大，并改善舒张功能障碍而不影响血压和收缩功能。总之，MCP-1 介导的巨噬细胞积聚通过 TGF-β 介导的过程在压力超负荷心脏的心肌纤维化中发挥作用。抑制炎症可能是预防高血压心脏心肌纤维化和由此导致的舒张功能障碍的新策略。
Excessive myocardial fibrosis deteriorates diastolic function in hypertensive hearts. Involvement of macrophages is suggested in fibrotic process in various diseased situations. We sought to examine the role of macrophages in myocardial remodeling and cardiac dysfunction in pressure-overloaded hearts. In Wistar rats with suprarenal aortic constriction, pressure overload induced perivascular macrophage accumulation and fibroblast proliferation with a peak at day 3, decreasing to lower levels by day 28. Myocyte chemoattractant protein (MCP)-1 mRNA was upregulated after day 1, peaking at day 3 and returning to insignificant levels by day 28, whereas transforming growth factor (TGF)-beta induction was observed after day 3, with a peak at day 7, and remained relatively elevated at day 28. After day 7, concentric left ventricular (LV) hypertrophy developed, associated with reactive fibrosis and myocyte hypertrophy. At day 28, echocardiography showed normal LV fractional shortening but decreased ratio of early to late filling wave of transmitral Doppler velocity, and hemodynamic studies revealed elevated LV end-diastolic pressure, suggesting normal systolic but impaired diastolic function. Chronic treatment with an anti-MCP-1 monoclonal neutralizing antibody inhibited not only macrophage accumulation but also fibroblast proliferation and TGF-beta induction. Furthermore, the neutralizing antibody attenuated myocardial fibrosis, but not myocyte hypertrophy, and ameliorated diastolic dysfunction without affecting blood pressure and systolic function. In conclusion, roles of MCP-1-mediated macrophage accumulation are suggested in myocardial fibrosis in pressure-overloaded hearts through TGF-beta-mediated process. Inhibition of inflammation may be a new strategy to prevent myocardial fibrosis and resultant diastolic dysfunction in hypertensive hearts.