Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5
Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5
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DOI：
10.1016/j.yjmcc.2014.08.008
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发表时间：
2014-11-01
影响因子：
5
通讯作者：
Tonnessen, Theis
中科院分区：
文献类型：
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作者：
Engebretsen, Kristin V. T.;Skardal, Kristine;Tonnessen, Theis
压力超负荷诱导的转化生长因子-β信号激活心脏成纤维细胞(CFB)，导致细胞外基质(ECM)蛋白合成增加，包括纤维化。过度的ECM积聚可能反过来影响心功能，从而导致心力衰竭的发生。本研究的目的是观察口服Alk5活性小分子抑制剂SM16对压力超负荷诱导的心肌纤维化的影响。主动脉结扎(AB)后一周，C57B1/6J小鼠随机分为标准饲料组和SM16饲料组。假手术动物作为对照。4周后处死小鼠，进行超声心动图和心血管磁共振检查。SM16在体内阻断AB诱导的Smad2的磷酸化，在体外阻断转化生长因子-β对CFB诱导的Smad2的磷酸化。有趣的是，在SM16治疗组中，马森三色和PMicro sirius Red染色的心肌左室组织显示AB后纤维化和胶原交联化的发展减少，这一点通过减少羟脯氨酸掺入得到证实。此外，SM16可抑制AB体内诱导和转化生长因子-β刺激后CFB中COLLA2、交联酶LOX、促纤维化糖蛋白SPARC和骨桥蛋白的mRNA表达。CFB减少ECM的合成，以及由于纤维化和胶原交联的延缓发展而导致的心肌僵硬的减少，可能是体内看到的舒张功能和心输出量的改善，以及SM16治疗后肺重量和ANP表达的减少。尽管SM16对心功能和心力衰竭的发展有这些有益的影响，但使用SM16治疗的小鼠表现出死亡率增加、左室扩张增加和心脏瓣膜炎症损伤，这可能限制SM16以及可能还有其他Alk5的小分子抑制剂作为未来治疗药物的使用。(C)2014爱思唯尔有限公司。保留所有权利。
Pressure overload-induced TGF-beta signaling activates cardiac fibroblasts (CFB) and leads to increased extracellular matrix (ECM) protein synthesis including fibrosis. Excessive ECM accumulation may in turn affect cardiac function contributing to development of heart failure. The aim of this study was to examine the effects of SM16, an orally active small molecular inhibitor of ALK5, on pressure overload-induced cardiac fibrosis. One week after aortic banding (AB), C57B1/6J mice were randomized to standard chow or chow with SM16. Sham operated animals served as controls. Following 4 weeks AB, mice were characterized by echocardiography and cardiovascular magnetic resonance before sacrifice. SM16 abolished phosphorylation of SMAD2 induced by AB in vivo and by TGF-beta in CFB in vitro. Interestingly, Masson Trichrome and Picrosirius Red stained myocardial left ventricular tissue revealed reduced development of fibrosis and collagen cross-linking following AB in the SM16 treated group, which was confirmed by reduced hydroxyproline incorporation. Furthermore, treatment with SM16 attenuated mRNA expression following induction of AB in vivo and stimulation with TGF-beta in CFB in vitro of Coll a2, the cross-linking enzyme LOX, and the pro-fibrotic glycoproteins SPARC and osteopontin. Reduced ECM synthesis by CFB and a reduction in myocardial stiffness due to attenuated development of fibrosis and collagen cross-linking might have contributed to the improved diastolic function and cardiac output seen in vivo, in combination with reduced lung weight and ANP expression by treatment with SM16. Despite these beneficial effects on cardiac function and development of heart failure, mice treated with SM16 exhibited increased mortality, increased LV dilatation and inflammatory heart valve lesions that may limit the use of SM16 and possibly also other small molecular inhibitors of ALK5, as future therapeutic drugs. (c) 2014 Elsevier Ltd. All rights reserved.