Humeres Claudio, Venugopal Harikrishnan, Frangogiannis Nikolaos G
The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.
The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.
Curr Opin Pharmacol. 2022 Jun;64:102207. doi: 10.1016/j.coph.2022.102207. Epub 2022 Mar 31.
In infarcted and failing hearts, TGF-β superfamily members play an important role in regulation of inflammatory, reparative, fibrogenic, and hypertrophic responses through activation of Smad-dependent and Smad-independent cascades. This review manuscript discusses the mechanisms of regulation and role of Smad pathways in myocardial infarction and in heart failure. Cardiomyocyte-specific Smad1 activation exerts protective anti-apoptotic actions following ischemia/reperfusion. In contrast, the role of the Smad1/5/8 cascade in reparative, immune, and vascular cells infiltrating the infarcted heart is unknown. Smad3, but not Smad2 is implicated in repair of the infarcted heart, by activating reparative myofibroblasts and by promoting anti-inflammatory transition in macrophages. However, prolonged activation of Smad3 may promote adverse remodeling and fibrosis. The inhibitory Smad, Smad7 restrains TGF-β-induced fibroblast activation, but also exerts TGF-independent actions through inhibition of receptor tyrosine kinase signaling. Cell-specific approaches targeting Smad pathways may hold therapeutic promise in myocardial infarction and in heart failure.
在梗死和衰竭的心脏中，转化生长因子-β（TGF-β）超家族成员通过激活依赖Smad和不依赖Smad的信号级联反应，在调节炎症、修复、纤维化和肥大反应中发挥重要作用。这篇综述文章讨论了Smad信号通路在心肌梗死和心力衰竭中的调节机制及作用。心肌细胞特异性的Smad1激活在缺血/再灌注后发挥保护性抗凋亡作用。相比之下，Smad1/5/8信号级联在梗死心脏中浸润的修复、免疫和血管细胞中的作用尚不清楚。Smad3而非Smad2通过激活修复性肌成纤维细胞和促进巨噬细胞的抗炎转变，参与梗死心脏的修复。然而，Smad3的长期激活可能促进不良重塑和纤维化。抑制性Smad，即Smad7，可抑制TGF-β诱导的成纤维细胞激活，但也通过抑制受体酪氨酸激酶信号传导发挥不依赖TGF-β的作用。针对Smad信号通路的细胞特异性方法可能在心肌梗死和心力衰竭的治疗中具有前景。
