Fontes Magda S C, Kessler Elise L, van Stuijvenberg Leonie, Brans Maike A, Falke Lucas L, Kok Bart, Leask Andrew, van Rijen Harold V M, Vos Marc A, Goldschmeding Roel, van Veen Toon A B
Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
J Mol Cell Cardiol. 2015 Nov;88:82-90. doi: 10.1016/j.yjmcc.2015.09.015. Epub 2015 Sep 26.
One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. However, recent studies have questioned the role of CTGF as a pro-fibrotic factor. Therefore, we aimed to investigate the effect of CTGF on cardiac fibrosis, and on functional, structural, and electrophysiological parameters in a mouse model of CTGF knockout (KO) and chronic pressure overload.
A new mouse model of global conditional CTGF KO induced by tamoxifen-driven deletion of CTGF, was subjected to 16weeks of chronic pressure overload via transverse aortic constriction (TAC, control was sham surgery). CTGF KO TAC mice presented with hypertrophic hearts, and echocardiography revealed a decrease in contractility on a similar level as control TAC mice. Ex vivo epicardial mapping showed a low incidence of pacing-induced ventricular arrhythmias (2/12 in control TAC vs. 0/10 in CTGF KO TAC, n.s.) and a tendency towards recovery of the longitudinal conduction velocity of CTGF KO TAC hearts. Picrosirius Red staining on these hearts unveiled increased fibrosis at a similar level as control TAC hearts. Furthermore, genes related to fibrogenesis were also similarly upregulated in both TAC groups. Histological analysis revealed an increase in fibronectin and vimentin protein expression, a significant reduction in connexin43 (Cx43) protein expression, and no difference in NaV1.5 expression of CTGF KO ventricles as compared with sham treated animals.
Conditional CTGF inhibition failed to prevent TAC-induced cardiac fibrosis and hypertrophy. Additionally, no large differences were found in other parameters between CTGF KO and control TAC mice. With no profound effect of CTGF on fibrosis formation, other factors or pathways are likely responsible for fibrosis development.
心脏适应性重塑的主要促成因素之一是纤维化。结缔组织生长因子（CTGF）是一种基质细胞蛋白，由心肌细胞和成纤维细胞分泌到心脏细胞外基质中，常与纤维化的发展相关。然而，最近的研究对CTGF作为促纤维化因子的作用提出了质疑。因此，我们旨在研究CTGF基因敲除（KO）和慢性压力超负荷小鼠模型中CTGF对心脏纤维化以及功能、结构和电生理参数的影响。
通过他莫昔芬驱动的CTGF缺失诱导的新型全球条件性CTGF基因敲除小鼠模型，经横向主动脉缩窄（TAC，对照组为假手术）进行16周的慢性压力超负荷实验。CTGF基因敲除TAC小鼠出现心脏肥大，超声心动图显示其收缩力下降程度与对照TAC小鼠相似。离体心外膜标测显示，起搏诱导的室性心律失常发生率较低（对照TAC组为2/12，CTGF基因敲除TAC组为0/10，无统计学差异），且CTGF基因敲除TAC心脏的纵向传导速度有恢复趋势。对这些心脏进行天狼星红染色发现，纤维化程度增加，与对照TAC心脏相似。此外，两个TAC组中与纤维生成相关的基因也同样上调。组织学分析显示，与假手术处理的动物相比，CTGF基因敲除心室中纤连蛋白和波形蛋白的蛋白表达增加，连接蛋白43（Cx43）的蛋白表达显著降低，而NaV1.5表达无差异。
条件性CTGF抑制未能预防TAC诱导的心脏纤维化和肥大。此外，CTGF基因敲除小鼠和对照TAC小鼠在其他参数上未发现大的差异。由于CTGF对纤维化形成没有显著影响，其他因素或途径可能是纤维化发展的原因。
