Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis
| Autor: | Estibaliz Castillero, Hirokazu Akashi, Ira Schlosberg, Alexandra Sperry, H. Lee Sweeney, Shunichi Homma, Karina Guaman, Isaac George, P. Christian Schulze, Adam Recht, Ziad A. Ali, Ruiping Ji, Catherine Wang, Paolo C. Colombo, Xianghai Liao, Xiaokan Zhang, Marc Najjar, Giovanni Ferrari, Lea Maria Brandstetter, Marcia Gailes |
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| Rok vydání: | 2019 |
| Předmět: |
Cardiac function curve
Male medicine.medical_specialty Physiology Cardiac fibrosis Activin Receptors Type II Myocardial Infarction Myocardial Ischemia Receptor Transforming Growth Factor-beta Type I Myostatin Sarcoplasmic Reticulum Calcium-Transporting ATPases Mice Fibrosis Physiology (medical) Internal medicine Natriuretic Peptide Brain medicine Animals Myocardial infarction Phosphorylation biology Ventricular Remodeling business.industry Myocardium Editorial Focus medicine.disease Ligand (biochemistry) Mice Inbred C57BL Endocrinology Echocardiography Heart failure Unfolded protein response biology.protein Physical Endurance Mitogen-Activated Protein Kinases Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | Am J Physiol Heart Circ Physiol |
| ISSN: | 1522-1539 |
| Popis: | Myostatin (MSTN) is a transforming growth factor (TGF)-β 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/TGFβ receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFβ 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, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) 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. |
| Databáze: | OpenAIRE |
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