Collagen cross-linking is an important step in optimal scar formation. Myocardial infarction (MI) results in loss of cardiomyocytes that are replaced with a scar (infarct) tissue. Disintegrin and metalloproteinases (ADAMs) are membrane-bound proteases that can interact with molecules intra- and extra-cellularly to mediate various cellular functions. ADAM15 is expressed in the myocardium, however its function in heart disease has been poorly explored. We utilized mice lacking ADAM15 (Adam15^−/−) and wildtype (WT) mice. MI, induced by ligation of the left anterior descending artery, resulted in a transient but significant rise in ADAM15 protein in the WT myocardium at 3-days. Following MI, Adam15^−/− mice exhibited markedly higher rate of left ventricular (LV) rupture compared to WT mice (66% vs. 15%, p<0.05). Echocardiography and strain analyses showed worsened LV dysfunction in Adam15^−/− mice at 3days, prior to the onset of LV rupture. Second harmonic generation imaging revealed significant disarray and reduction in fibrillar collagen density in Adam15^−/− compared to WT hearts. This was associated with lower insoluble and higher soluble collagen fractions, reduced cross-linking enzyme, lysyl oxidase-1 (LOX-1), and fibronectin which is required for LOX-1 function, in Adam15^−/−-MI hearts. Post-MI myocardial inflammation was comparable between the genotypes. In vitro, primary adult cardiac fibroblasts from Adam15^−/− mice showed suppressed activation in response to ischemia (hypoxia+nutrient depletion) compared to WT fibroblasts. Adam15-deficiency was associated with reduced PAK1(p21-activated kinase-1) levels, a regulator of fibronectin and LOX-1 expression. In female mice, the rate of post-MI LV rupture, PAK1 signaling, LOX-1 and fibronectin protein levels were comparable between Adam15^−/− and WT, indicating less impact of ADAM15 loss in females post- MI. This study reports a novel function for ADAM15 in collagen cross-linking and optimal scar formation post-MI which may also apply to scar formation in other tissues.

胶原交联是最佳疤痕形成的重要步骤。心肌梗塞 (MI) 导致心肌细胞丢失，并被瘢痕（梗塞）组织取代。去整合素和金属蛋白酶 (ADAM) 是膜结合蛋白酶，可以与细胞内和细胞外的分子相互作用以介导各种细胞功能。ADAM15 在心肌中表达，但其在心脏病中的功能研究很少。我们使用了缺乏 ADAM15 ( Adam15 ^-/- ) 的小鼠和野生型 (WT) 小鼠。由左前降支结扎引起的 MI 导致 WT 心肌中的 ADAM15 蛋白在 3 天时短暂但显着升高。继 MI，Adam15 ^-/-与 WT 小鼠相比，小鼠的左心室 (LV) 破裂率明显更高（66% 对 15%，p <0.05）。超声心动图和应变分析显示，Adam15 ^-/-小鼠在左室破裂前 3 天左室功能障碍恶化。二次谐波生成成像显示与 WT 心脏相比， Adam15 ^{-/-中的纤维状胶原密度显着混乱和降低。}这与Adam15 ^-/- -MI 心脏中较低的不溶性和较高可溶性胶原蛋白组分、减少的交联酶、赖氨酰氧化酶-1 (LOX-1) 和 LOX-1 功能所需的纤连蛋白有关。MI后心肌炎症在基因型之间具有可比性。体外与 WT 成纤维细胞相比，来自Adam15 ^-/-小鼠的原代成年心脏成纤维细胞表现出对缺血（缺氧+营养耗竭）的抑制激活。Adam15 缺陷与降低的 PAK1（p21 激活激酶 1）水平、纤连蛋白和 LOX-1 表达的调节剂有关。在雌性小鼠中， Adam15 ^-/-和 WT之间的 MI 后 LV 破裂率、PAK1 信号传导、LOX-1 和纤连蛋白水平相当，表明 ADAM15 损失对 MI 后雌性小鼠的影响较小。这项研究报告了 ADAM15 在胶原交联和 MI 后最佳瘢痕形成方面的新功能，这也可能适用于其他组织中的瘢痕形成。