Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Australia.
Int J Cardiol. 2013 Sep 30;168(2):1174-85. doi: 10.1016/j.ijcard.2012.11.067. Epub 2012 Dec 6.
Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model.
Collagen synthesis in NCF was determined by (3)H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200mg/kg/day) or vehicle for a further 4 weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment.
Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.
心肌梗死后心室非梗死区（NIZ）细胞外基质的病理性沉积是心脏重构和心力衰竭的主要原因。FT011 是一种新型抗纤维化化合物，本文评估了其在新生心肌成纤维细胞（NCF）和实验性心肌梗死模型中的疗效。
用（3）H-脯氨酸掺入法检测 TGF-β或血管紧张素 II（Ang II）刺激后的 NCF 胶原合成。FT011 呈剂量依赖性抑制两种药物的胶原合成。在体内，Sprague Dawley 大鼠进行左前降支结扎或假手术，一周后随机接受 FT011（200mg/kg/天）或载体治疗 4 周。进行超声心动图和心导管检查，并采集组织进行胶原、心肌细胞肥大、间质巨噬细胞积累和 Smad2 磷酸化的组织学分析。使用原位杂交和 RT-PCR 分别测量胶原 I 和 III 和 TGF-β的 mRNA 表达。与载体治疗相比，FT011 治疗与改善的心脏功能（射血分数增加、缩短分数和预负荷可恢复的工作）和心肌重构（舒张末期和收缩末期左心室直径和容积减少）相关。与载体治疗相比，FT011 显著减少了 NIZ 中的胶原基质沉积、心肌细胞肥大和间质巨噬细胞浸润以及 I 和 III 型胶原的 mRNA 表达。
MI 大鼠的抗纤维化治疗用 FT011 减轻了纤维化并保持了收缩功能。
