Kuwahara Fumitaka, Kai Hisashi, Tokuda Keisuke, Takeya Motohiro, Takeshita Akira, Egashira Kensuke, Imaizumi Tsutomu
Internal Medicine III and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
Hypertension. 2004 Apr;43(4):739-45. doi: 10.1161/01.HYP.0000118584.33350.7d. Epub 2004 Feb 16.
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.
过度的心肌纤维化会使高血压心脏的舒张功能恶化。在各种疾病状态下的纤维化过程中提示有巨噬细胞参与。我们试图研究巨噬细胞在压力负荷过重心脏的心肌重塑和心脏功能障碍中的作用。在患有肾上腺主动脉缩窄的Wistar大鼠中，压力负荷导致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。心肌细胞趋化因子蛋白（MCP）-1 mRNA在第1天后上调，在第3天达到峰值，并在第28天恢复到无显著意义的水平，而转化生长因子（TGF）-β在第3天后诱导出现，在第7天达到峰值，并在第28天仍相对升高。第7天后，出现同心性左心室（LV）肥厚，伴有反应性纤维化和心肌细胞肥大。在第28天，超声心动图显示左心室分数缩短正常，但二尖瓣多普勒速度的早期与晚期充盈波比值降低，血流动力学研究显示左心室舒张末期压力升高，提示收缩功能正常但舒张功能受损。用抗MCP-1单克隆中和抗体进行慢性治疗不仅抑制了巨噬细胞积聚，还抑制了成纤维细胞增殖和TGF-β诱导。此外，中和抗体减轻了心肌纤维化，但未减轻心肌细胞肥大，并改善了舒张功能障碍，而不影响血压和收缩功能。总之，提示在压力负荷过重心脏的心肌纤维化中，MCP-1介导的巨噬细胞积聚通过TGF-β介导的过程发挥作用。抑制炎症可能是预防高血压心脏心肌纤维化及由此导致的舒张功能障碍的一种新策略。
