Koshman Yevgeniya E, Sternlicht Mark D, Kim Taehoon, O'Hara Christopher P, Koczor Christopher A, Lewis William, Seeley Todd W, Lipson Kenneth E, Samarel Allen M
The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States.
FibroGen, Inc., San Francisco, CA 94158, United States.
J Mol Cell Cardiol. 2015 Dec;89(Pt B):214-22. doi: 10.1016/j.yjmcc.2015.11.003. Epub 2015 Nov 5.
Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective tissue growth factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic functions in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling was elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.
与扩张型心肌病（DCM）相关的心脏结构变化包括心肌细胞肥大和心肌纤维化。结缔组织生长因子（CTGF）与组织重塑有关，且在衰竭心脏中高表达。我们的目的是在蛋白激酶Cε（PKCε）基因的DCM小鼠模型中，测试抑制CTGF是否会改变心脏重塑进程并保留心脏功能。在心肌细胞中组成性表达活性PKCε的转基因小鼠在3月龄时出现心脏功能障碍，随后进展为心脏纤维化、心力衰竭，并增加死亡率。从3月龄开始，用针对CTGF的中和单克隆抗体（FG - 3149）对PKCε小鼠再治疗3个月。抑制CTGF可显著改善PKCε小鼠的左心室（LV）收缩和舒张功能，并减缓LV扩张进程。使用基因芯片和定量PCR技术发现，与组织重塑相关的许多基因在PKCε小鼠中表达升高，但通过抑制CTGF可使其显著降低。然而，总胶原沉积并未减弱。在PKCε小鼠中抑制CTGF可显著改善LV功能，这一观察结果表明抑制CTGF可能对DCM患者有益。有必要进行更多研究来探索这一潜在益处。
