Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
J Mol Cell Cardiol. 2012 Jan;52(1):273-82. doi: 10.1016/j.yjmcc.2011.11.001. Epub 2011 Nov 9.
Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.
心脏细胞外基质（ECM）的重塑是心肌梗死后（MI）愈合和心室适应的一个重要组成部分，但潜在机制仍不完全清楚。纤连蛋白-2 是一种在心脏发育和皮肤伤口愈合过程中上调的 ECM 蛋白，但缺乏纤连蛋白-2的小鼠并没有表现出任何可识别的表型异常。为了研究纤连蛋白-2 缺乏对 MI 后 ECM 重塑的影响，我们通过永久性冠状动脉结扎在纤连蛋白-2 缺失和野生型小鼠中诱导实验性 MI。纤连蛋白-2 在野生型小鼠的梗死边界区表达上调。MI 后急性心肌组织反应，包括炎症细胞浸润和 ECM 蛋白在梗死边界区的合成和沉积，在纤连蛋白-2 缺失小鼠中明显减弱。然而，由于心脏破裂的频率较低和左心室功能得到保留，纤连蛋白-2 缺失小鼠的 MI 后生存率明显高于野生型小鼠。与野生型相比，纤连蛋白-2 缺失小鼠的 MI 后 TGF-β 信号和 ECM 重塑的上调明显减弱。纤连蛋白-2 缺失的心脏成纤维细胞中 TGF-β 信号对血管紧张素 II 的反应也减弱。这些研究首次提供了证据，证明纤连蛋白-2 缺失导致 MI 后 TGF-β 信号的上调减少，并防止心室功能障碍，这表明纤连蛋白-2 可能是一种潜在的治疗靶点，可减轻心室重塑的进展。
