From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (C.G.-Q., M.C., A.B., P.K., D.-W.L., A.S., O.F., M.D., A.S., N.G.F.); and Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., A.B., M.D., N.G.F.).
Circ Res. 2013 Dec 6;113(12):1331-44. doi: 10.1161/CIRCRESAHA.113.302593. Epub 2013 Sep 30.
Diabetes mellitus is associated with cardiac fibrosis. Matricellular proteins are induced in fibrotic conditions and modulate fibrogenic and angiogenic responses by regulating growth factor signaling.
Our aim was to test the hypothesis that the prototypical matricellular protein thrombospondin (TSP)-1, a potent angiostatic molecule and crucial activator of transforming growth factor-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. To study the role of TSP-1 in remodeling of the diabetic heart, we generated and characterized db/db TSP-1(-/-) (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 nonprogressive systolic dysfunction. Chamber dilation in dbTSP mice was associated with decreased myocardial collagen content and accentuated matrix metalloproteinase-2 and -9 activity. TSP-1 disruption did not affect inflammatory gene expression and activation of transforming growth factor-β/small mothers against decapendaplegic signaling in the db/db myocardium. In cardiac fibroblasts populating collagen pads, TSP-1 incorporation into the matrix did not activate transforming growth factor-β responses, but inhibited leptin-induced matrix metalloproteinase-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.
糖尿病与心脏纤维化有关。细胞外基质蛋白在纤维化条件下被诱导，并通过调节生长因子信号来调节纤维生成和血管生成反应。
我们的目的是检验这样一个假设，即典型的细胞外基质蛋白血小板反应蛋白-1（TSP-1），一种有效的血管生成抑制分子和转化生长因子-β的关键激活剂，可能在糖尿病心脏重构中发挥关键作用。
肥胖型糖尿病 db/db 小鼠的心肌间质和血管周围 TSP-1 表达显著上调。为了研究 TSP-1 在糖尿病心脏重构中的作用，我们构建并鉴定了 db/db TSP-1(-/-)（dbTSP）小鼠。TSP-1 缺失对 db/db 动物的体重增加和代谢功能没有显著影响。与 db/db 动物相比，dbTSP 小鼠的左心室扩张更为明显，且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减少和基质金属蛋白酶-2 和 -9 活性增强有关。TSP-1 缺失不影响炎症基因表达和转化生长因子-β/小 mothers against decapendaplegic 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 整合到基质中不会激活转化生长因子-β 反应，但会抑制瘦素诱导的基质金属蛋白酶-2 激活。TSP-1 缺失消除了 db/db 小鼠年龄相关的毛细血管稀疏，从而减弱了心肌中血管生成素-2 的上调，血管生成素-2 是一种诱导血管退化的介质。在体外，TSP-1 刺激增加了巨噬细胞而不是内皮细胞的血管生成素-2 合成。
糖尿病心脏中 TSP-1 的上调通过对心脏成纤维细胞发挥基质保护作用来防止心室扩张，并通过可能涉及血管生成素-2 上调的作用来介导毛细血管稀疏。
