Tumor necrosis factor-α mediates cardiac remodeling and ventricular dysfunction after pressure overload state
Tumor necrosis factor-α mediates cardiac remodeling and ventricular dysfunction after pressure overload state
复制标题
DOI：
10.1161/circulationaha.106.643585
复制
发表时间：
2007-03-20
期刊：
影响因子：
37.8
通讯作者：
Liu, Peter P.
中科院分区：
文献类型：
--
作者：
Sun, Mei;Chen, Manyin;Liu, Peter P.
背景-压力超负荷伴随心肌细胞凋亡、肥大和炎症/纤维化反应，导致心室重构和心力衰竭。尽管对这一过程是如何调节的不完全理解，但已知心肌中主动脉缩窄后肿瘤坏死因子（TNF）-α的上调。在本研究中，我们测试了我们的假设，TNF-α调节心脏炎症反应，细胞外基质的稳态，心室肥大的机械超载，并有助于ventricular dysfunction.Methods和Results-C57/BL野生型小鼠和TNF-敲除（TNF-/-）小鼠进行降主动脉结扎或假手术。与假手术小鼠相比，野生型小鼠主动脉缩窄显示心脏TNF-α水平显著增加，这与第2周的心肌细胞凋亡、炎症反应和心脏肥大以及第2周和第6周的基质金属蛋白酶-9活性显著升高和心功能受损一致。与野生型小鼠相比，TNF-/-小鼠的主动脉结扎显示减弱的心脏凋亡，肥大，炎症反应和修复性纤维化。这些小鼠还表现出降低心脏基质金属蛋白酶-9活性和改善心脏功能。结论-本研究的结果表明，TNF-α有助于通过调节心脏修复和重塑，导致心室功能障碍的压力超负荷过程中不利的左心室重塑。
Background-Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling and heart failure. Despite incomplete understanding of how this process is regulated, the upregulation of tumor necrosis factor (TNF)-alpha after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-alpha regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction.Methods and Results-C57/BL wild-type mice and TNF-knockout (TNF-/-) mice underwent descending aortic banding or sham operation. Compared with sham-operated mice, wild-type mice with aortic banding showed a significant increase in cardiac TNF-alpha levels, which coincided with myocyte apoptosis, inflammatory response, and cardiac hypertrophy in week 2 and a significant elevation in matrix metalloproteinase-9 activity and impaired cardiac function in weeks 2 and 6. Compared with wild-type mice with aortic banding, TNF-/- mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis. These mice also showed reduced cardiac matrix metalloproteinase-9 activity and improved cardiac function.Conclusions-Findings from the present study have suggested that TNF-alpha contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.