Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice
Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice
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DOI：
10.1186/s13395-020-00230-9
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发表时间：
2020-04-25
期刊：
影响因子：
4.9
通讯作者：
Kinugawa, Shintaro
中科院分区：
文献类型：
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作者：
Kakutani, Naoya;Takada, Shingo;Kinugawa, Shintaro
转化生长因子β (tgf - β)-Smad2/3是纤维化的主要信号通路，其特征是包括胶原在内的细胞外基质（ECM）成分的过度产生和积累。虽然ECM是骨骼肌的重要组成部分，但纤维化可能对肌肉功能有害。另一方面，我们之前的研究表明，在心肌梗死（MI）小鼠中，作用于tgf - β - smad2 /3信号上游的血管紧张素II水平升高。在本研究中，我们发现心肌梗死小鼠的骨骼肌纤维化程度高于对照组小鼠，并对其机制进行了研究。此外，我们给予基于上述机制的抑制剂，并研究其对骨骼肌纤维化的预防作用。方法制备雄性心肌梗死小鼠C57BL/ 6j，以假手术小鼠为对照。通过小天狼星红染色分析心肌梗死后骨骼肌纤维化的时间过程（第1,3,7和14天）。然后将小鼠分为3组：sham + vehicle (sham + Veh), MI + Veh， MI +赖诺普利（一种血管紧张素转换酶[ACE]抑制剂，20 mg/kg体重/天，饮用水；MI + Lis）。Lis或Veh从术后立即至术后14天给予治疗。结果术后3 ~ 14 d，心肌梗死小鼠骨骼肌纤维化程度明显高于假手术小鼠。虽然MI + Lis小鼠的死亡率低于MI + Veh小鼠，但在14天时，两组之间的心功能没有差异。与Sham + Veh小鼠相比，MI + Veh小鼠骨骼肌纤维化和羟脯氨酸（胶原含量的关键标志物）显著增加。与这些结果一致的是，与假手术小鼠相比，心肌梗死小鼠术后早期时间点（术后1-7天）骨骼肌中tgf - β和磷酸化Smad2/3的蛋白表达以及术后14天的血管紧张素II的表达均有所增加。MI + Lis小鼠的这些损伤得到改善，对自发体力活动、肌肉力量、肌肉重量和血压没有任何影响。结论ACE抑制剂可预防心肌梗死后早期骨骼肌纤维化的增加，为改善心脏病骨骼肌异常提供了新的治疗靶点。
Background Transforming growth factor beta (TGF-beta)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-beta-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. Methods Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery. Results Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-beta and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. Conclusions ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.