Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload
Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload
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DOI：
10.1096/fj.11-190728
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发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Stenina, Olga I.
中科院分区：
文献类型：
--
作者：
Frolova, Ella G.;Sopko, Nikolai;Stenina, Olga I.
血小板反应蛋白-4（TSP-4）的表达在啮齿动物模型和人类的肥大和衰竭心脏中显著增加。本研究的目的是探讨TSP-4在心脏中的功能。对TSP-4敲除（Thbs 4（-/-））和野生型（WT）小鼠进行横向主动脉缩窄（TAC）以增加左心室负荷。2周后，Thbs 4（-/-）小鼠的心脏重量/体重比显著高于WT小鼠。TAC Thbs 4（-/-）小鼠心脏重量的额外增加是由于细胞外基质（ECM）沉积增加。敲除小鼠的间质胶原水平较高，但心肌细胞的大小和心肌细胞凋亡不受TSP-4缺乏的影响，这表明反应性纤维化增加是心脏重量增加的主要原因。Thbs 4（-/-）小鼠中ECM沉积的增加伴随着心脏功能参数的变化和血管密度的降低。已知对心肌重塑有影响的炎症和纤维化基因的表达由于体内TSP-4缺乏和体外细胞与重组TSP-4孵育而改变。因此，TSP-4参与调节心脏对压力超负荷的适应性反应，表明其在心肌重塑中的重要作用。我们的研究表明TSP-4对心脏功能的直接影响，并确定其对心脏重塑影响的机制。Frolova，E. G.，Sopko，N.，布莱赫湖，Popovic，Z. B.，李杰，Vasanji，A.，Drumm，C.，克鲁科韦茨岛贾恩，M。K.，佩恩，M。美国，Plow，E. F.、斯特尼纳岛I.凝血酶敏感蛋白-4调节压力超负荷时心肌纤维化和重塑。FASEB J.26，2363-2373（2012）. www.fasebj.org
Thrombospondin-4 (TSP-4) expression increases dramatically in hypertrophic and failing hearts in rodent models and in humans. The aim of this study was to address the function of TSP-4 in the heart. TSP-4-knockout (Thbs4(-/-)) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) to increase left ventricle load. After 2 wk, Thbs4(-/-) mice had a significantly higher heart weight/body weight ratio than WT mice. The additional increase in the heart weight in TAC Thbs4(-/-) mice was due to increased deposition of extracellular matrix (ECM). The levels of interstitial collagens were higher in the knockout mice, but the size of cardiomyocytes and apoptosis in the myocardium was unaffected by TSP-4 deficiency, suggesting that increased reactive fibrosis was the primary cause of the higher heart weight. The increased ECM deposition in Thbs4(-/-) mice was accompanied by changes in functional parameters of the heart and decreased vessel density. The expression of inflammatory and fibrotic genes known to be influential in myocardial remodeling changed as a result of TSP-4 deficiency in vivo and as a result of incubation of cells with recombinant TSP-4 in vitro. Thus, TSP-4 is involved in regulating the adaptive responses of the heart to pressure overload, suggesting its important role in myocardial remodeling. Our study showed a direct influence of TSP-4 on heart function and to identify the mechanism of its effects on heart remodeling.-Frolova, E. G., Sopko, N., Blech, L., Popovic, Z. B., Li, J., Vasanji, A., Drumm, C., Krukovets, I., Jain, M. K., Penn, M. S., Plow, E. F., Stenina, O. I. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload. FASEB J. 26, 2363-2373 (2012). www.fasebj.org