Department of Pathology, Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
Department of Applied Biology, Division of In-Vivo Models and Testing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
Cell Biochem Funct. 2024 Jun;42(4):e4066. doi: 10.1002/cbf.4066.
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.
赖氨酰氧化酶介导的胶原交联是心肌损伤后心肌成纤维细胞启动的心脏修复过程中的一种适应性机制。然而，过度交联会导致心脏壁变硬，从而损害左心室的收缩性能，导致心力衰竭。在这项研究中，我们研究了细胞外基质蛋白骨桥蛋白在调节心肌成纤维细胞中赖氨酰氧化酶对血管紧张素 II 和 TGFβ1 反应中的作用。我们的结果表明，骨桥蛋白沉默消除了血管紧张素 II 和 TGFβ1 介导的赖氨酰氧化酶上调。此外，骨桥蛋白表达的衰减导致赖氨酰氧化酶活性显著降低。骨桥蛋白下游的 ERK1/2 MAPK 信号通路被激活，进而转录上调血清反应因子，促进赖氨酰氧化酶的增强表达。在心肌梗死的体内大鼠模型中，也观察到骨桥蛋白与赖氨酰氧化酶之间存在正相关。骨桥蛋白和赖氨酰氧化酶在左心室富含胶原的纤维疤痕组织中的表达上调。值得注意的是，超声心动图数据显示左心室壁运动、射血分数和缩短分数降低，表明心脏壁变硬增强。这些发现揭示了骨桥蛋白在激活的心肌成纤维细胞引发的胶原交联中的机制作用。我们的发现表明骨桥蛋白可能是一个治疗靶点，以减少导致心力衰竭相关结构重塑的过度胶原交联。
