Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis
Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis
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DOI：
10.1152/ajpheart.00302.2019
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发表时间：
2020-02-01
影响因子：
4.8
通讯作者：
George, Isaac
中科院分区：
文献类型：
--
作者：
Castillero, Estibaliz;Akashi, Hirokazu;George, Isaac
肌生长抑制素（Myostatin，MSTs）是一种转化生长因子（transforming growth factor，TGF）-β超家族成员，在心肌重塑中起负调节作用。我们假设，抑制激活素II型受体（ACTRII），以减少MRF信号转导将减少实验性心力衰竭（HF）的病理性心脏重塑。C57 BL/6 J小鼠在麻醉下进行冠状动脉左前降支结扎以诱导心肌梗死（MI）或不结扎（假手术）。将MI和假手术动物各自随机分成接受ACTRII或ACTRII/TGF β受体信号传导抑制策略的组（n ≥ 10只小鼠/组）：1）myo-Fc组（每周10 mg/kg Myo-Fc）或2）Fol + TGFi组（每日12 μ g/kg卵泡抑素加2 mg/kg TGF β受体抑制剂），相对于对照。ACTRII/TGFBR信号传导抑制通过超声心动图保护心脏功能，并防止脑钠肽（BNP）增加。ACTRII/TGFBR抑制导致MI小鼠Akt磷酸化水平升高（P）和P-p38丝裂原活化蛋白激酶（MAPK）水平降低。在体外，Akt促进心肌细胞中P-SMAD 2、3、P-p38和BNP的调节。ACTRII/TGFBR抑制增加心肌梗死小鼠肌浆网/内质网Ca 2 +-ATP酶（SERCA 2a）水平，降低未折叠蛋白反应（UPR）标志物。ACTRII/TGFBR抑制与MI小鼠心脏纤维化和纤维化标志物、结缔组织生长因子（CTGF）、I型胶原蛋白、纤连蛋白、α-平滑肌肌动蛋白和基质金属蛋白酶（MMP）-12的减少相关。心肌细胞中的UPR标记物真核翻译起始因子-2 α（eIf 2 α）对MMP 2有直接的调节作用。我们的研究表明，ACTRII配体抑制对缺血性HF后的心脏信号传导和纤维化具有有益的作用。新&值得注意的是，激活素II型受体配体抑制导致心肌梗死小鼠的心脏功能得到保护，心脏纤维化减少，SERCA 2a水平提高，并预防未折叠蛋白反应。
Myostatin (MSTN) is a transforming growth factor (TGF)-beta superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups (n >= 10 mice/group) receiving an ACTRII or ACTRII/TGF beta receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 mu g/kg follistatin plus 2 mg/kg TGF beta receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, alpha-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2 alpha (eIf2 alpha) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF.NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.