Abstract：
Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFβ1. Our results indicated that periostin silencing abolished the angiotensin II and TGFβ1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.
摘要：
胶原交联,赖氨酰氧化酶介导，是心肌损伤后由心脏成纤维细胞启动的心脏修复过程的适应性机制。然而,过度交联导致心脏壁变硬，这会损害左心室的收缩特性并导致心力衰竭。在这项研究中,我们研究了骨膜素的作用,一种体细胞蛋白质，在响应血管紧张素II和TGFβ1的心脏成纤维细胞中赖氨酰氧化酶的调节中。我们的结果表明骨膜素沉默消除了血管紧张素II和TGFβ1介导的赖氨酰氧化酶的上调。此外，骨膜素表达的减弱导致赖氨酰氧化酶活性显着降低。骨膜素下游，发现ERK1/2MAPK信号被激活，反过来转录上调血清反应因子以促进赖氨酰氧化酶的增强表达。骨膜素-赖氨酰氧化酶缔合在心肌梗死的体内大鼠模型中也呈正相关。左心室富含胶原的纤维化瘢痕组织中骨膜素和赖氨酰氧化酶的表达上调。值得注意的是,超声心动图数据显示左心室壁运动减少，射血分数,和分数缩短，表明心脏壁硬化增强。这些发现揭示了骨膜素在活化的心脏成纤维细胞引发的胶原交联中的机制作用。我们的研究结果表明骨膜素可能是减少过度胶原交联的治疗靶标，这有助于与心力衰竭相关的结构重塑。
