Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation.
Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation.
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DOI：
10.1161/circresaha.113.302593
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发表时间：
2013-12-06
影响因子：
20.1
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
--
作者：
Gonzalez-Quesada C;Cavalera M;Biernacka A;Kong P;Lee DW;Saxena A;Frunza O;Dobaczewski M;Shinde A;Frangogiannis NG
糖尿病与心脏纤维化有关。基质细胞蛋白在纤维化条件下被诱导，并通过调节生长因子信号传导调节纤维化和血管生成反应。为了验证原型基质细胞蛋白血小板反应蛋白(TSP)-1，一种有效的血管抑制分子和TGF-β的关键激活剂，可能在糖尿病心脏重塑中发挥关键作用的假设。肥胖糖尿病db/db小鼠在心肌间质和血管周围空间表现出明显的TSP-1上调。为了研究TSP-1在糖尿病心脏重塑中的作用，我们建立了db/db TSP-1 null （dbTSP）小鼠并对其进行了表征。在db/db动物中，TSP-1的破坏对体重增加和代谢功能没有显著影响。与db/db动物相比，dbTSP小鼠左心室扩张增加，伴有轻度非进行性收缩功能障碍。dbTSP小鼠的心室扩张与心肌胶原含量降低和基质金属蛋白酶(MMP)-2和-9活性增强有关。阻断TSP-1不影响炎症基因表达和TGF-β/Smad信号在db/db心肌中的激活。在填充胶原垫的心脏成纤维细胞中，TSP-1掺入基质不激活TGF-β反应，但抑制瘦素诱导的MMP-2激活。在db/db小鼠中，TSP-1的破坏消除了年龄相关的毛细血管稀疏，减弱了血管生成素-2的心肌上调，血管生成素-2是一种诱导血管退化的介质。体外，TSP-1刺激增加巨噬细胞，但不增加内皮细胞，血管生成素-2的合成。糖尿病心脏中TSP-1的上调通过对心脏成纤维细胞施加基质保护作用来阻止心室扩张，并通过可能涉及血管生成素-2上调的作用介导毛细血管稀疏。
Diabetes is associated with cardiac fibrosis. Matricellular proteins are induced in fibrotic conditions and modulate fibrogenic and angiogenic responses by regulating growth factor signaling. To test the hypothesis that the prototypical matricellular protein thrombospondin (TSP)-1, a potent angiostatic molecule and crucial activator of TGF-β, may play a key role in remodeling of the diabetic heart. Obese diabetic db/db mice exhibited marked myocardial TSP-1 upregulation in the interstitial and perivascular space. In order to study the role of TSP-1 in remodeling of the diabetic heart we generated and characterized db/db TSP-1 null (dbTSP) mice. TSP-1 disruption did not significantly affect weight gain and metabolic function in db/db animals. When compared with db/db animals, dbTSP mice had increased left ventricular dilation associated with mild non-progressive systolic dysfunction. Chamber dilation in dbTSP mice was associated with decreased myocardial collagen content and accentuated Matrix Metalloproteinase (MMP)-2 and -9 activity. TSP-1 disruption did not affect inflammatory gene expression and activation of TGF-β/Smad signaling in the db/db myocardium. In cardiac fibroblasts populating collagen pads, TSP-1 incorporation into the matrix did not activate TGF-β responses, but inhibited leptin-induced MMP-2 activation. TSP-1 disruption abrogated age-associated capillary rarefaction in db/db mice, attenuating myocardial upregulation of angiopoietin-2, a mediator that induces vascular regression. In vitro, TSP-1 stimulation increased macrophage, but not endothelial cell, angiopoietin-2 synthesis. TSP-1 upregulation in the diabetic heart prevents chamber dilation by exerting matrix-preserving actions on cardiac fibroblasts and mediates capillary rarefaction through effects that may involve angiopoietin-2 upregulation.