Gravning Jørgen, Ahmed Mohammed Shakil, von Lueder Thomas G, Edvardsen Thor, Attramadal Håvard
Institute for Surgical Research, Oslo University Hospital, Rikshospitalet and University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
Int J Cardiol. 2013 Oct 3;168(3):2049-56. doi: 10.1016/j.ijcard.2013.01.165. Epub 2013 Feb 26.
Myocardial CCN2/CTGF (connective tissue growth factor) is strongly induced in heart failure (HF) and acts as a cardioprotective factor in ischemia/reperfusion injury. However, its functional role in myocardial hypertrophy remains unresolved.
Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate control (NLC) mice were subjected to chronic pressure-overload by abdominal aortic banding. After 4weeks of persistent pressure-overload, a time point at which compensatory hypertrophy of the left ventricle (LV) prevails, Tg-CTGF mice displayed diminished increase of LV mass compared with NLC. At study end-point after 12 weeks of sustained aortic constriction, the mice displayed LV dilatation and reduced cardiac function. Repeated transthoracic echocardiography during the 12 weeks of chronic pressure-overload, revealed attenuation of LV dilatation and virtually sustained systolic function in Tg-CTGF mice compared with NLC mice. Also, increase of LV mass was blunted in Tg-CTGF versus NLC mice at study end-point. Consistently, increases of myocardial ANP, BNP and skeletal α-actin mRNA levels were blunted in Tg-CTGF mice subjected to chronic pressure-overload. Furthermore, cardiac myocytes from Tg-CTGF mice displayed increased phospho-NFATc2 levels and attenuated hypertrophic response upon stimulation with α1-adrenoceptor agonist, indicating that CTGF attenuates hypertrophic signaling in cardiac myocytes. Increase of myocardial collagen contents in mice subjected to aortic banding was similar in Tg-CTGF and NLC mice, indicating that CTGF have minimal impact on myocardial collagen deposition.
This study provides novel evidence that CTGF attenuates cardiac hypertrophy upon chronic pressure-overload due to inhibition of signaling mechanisms that promote pathologic myocardial hypertrophy.
心肌CCN2/结缔组织生长因子（CTGF）在心力衰竭（HF）中被强烈诱导，并在缺血/再灌注损伤中作为一种心脏保护因子发挥作用。然而，其在心肌肥大中的功能作用仍未明确。
通过腹主动脉缩窄使心脏特异性过表达CTGF的转基因小鼠（Tg-CTGF）和同窝非转基因对照（NLC）小鼠承受慢性压力超负荷。在持续压力超负荷4周后，即左心室（LV）代偿性肥大占优势的时间点，与NLC相比，Tg-CTGF小鼠的LV质量增加减少。在持续主动脉缩窄12周后的研究终点，小鼠出现LV扩张和心功能降低。在慢性压力超负荷的12周期间重复进行经胸超声心动图检查，结果显示与NLC小鼠相比，Tg-CTGF小鼠的LV扩张减弱且收缩功能基本维持。此外，在研究终点时，Tg-CTGF小鼠与NLC小鼠相比，LV质量的增加也受到抑制。同样，在承受慢性压力超负荷的Tg-CTGF小鼠中，心肌ANP、BNP和骨骼肌α-肌动蛋白mRNA水平的升高也受到抑制。此外，来自Tg-CTGF小鼠的心肌细胞显示磷酸化NFATc2水平升高，并且在用α1-肾上腺素能受体激动剂刺激后肥大反应减弱，这表明CTGF减弱了心肌细胞中的肥大信号传导。在接受主动脉缩窄的小鼠中，Tg-CTGF小鼠和NLC小鼠的心肌胶原含量增加相似，这表明CTGF对心肌胶原沉积的影响最小。
本研究提供了新的证据，表明CTGF通过抑制促进病理性心肌肥大的信号传导机制，减轻慢性压力超负荷引起的心脏肥大。
