title: Involvement of the dual-specificity tyrosine phosphorylation-regulated kinase 1A-alternative splicing factor-calcium/calmodulin-dependent protein kinase IIδ signaling pathway in myocardial infarction-induced heart failure of rats.
abstract: BACKGROUND
  Alternative splicing factor (ASF)-regulated alternative splicing of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) plays an important role in pathologic cardiac remodeling. ASF can be phosphorylated by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). This study aimed to investigate the possible involvement of the Dyrk1A-ASF-CaMKIIδ signaling pathway in the progression of myocardial infarction (MI)-induced heart failure (HF).
  
  
  RESULTS
  MI in rats was induced by means of left anterior descending coronary artery ligation. Seven weeks after MI, the increase in left ventricular internal diameter at end-diastole (LVIDd), and the decrease in both ejection fraction (EF) and fractional shortening (FS) indicated that MI rats had developed HF. Quantitative real time reverse-transcription polymerase chain reaction indicated the dysregulation of CaMKIIδ alternative splicing, ie, up-regulation of CaMKIIδA and CaMKIIδC and down-regulation of CaMKIIδB in the hearts of HF rats. Electrophoresis and immunostaining revealed that HF activated the phosphorylation of ASF and affected its subcellular localization. Western blot analysis demonstrated a significant elevation in the activity and expression of Dyrk1A in HF rats. Inversely, treatment of MI-induced HF rats with Dyrk1A inhibitor, either harmine or EGCG, improved the symptoms of HF, reversed the molecular changes of Dyrk1A and ASF, and regulated alternative splicing of CaMKIIδ in HF rats.
  
  
  CONCLUSIONS
  Enhanced activation of Dyrk1A-ASF-CaMKIIδ signaling pathway may underlie the mechanisms of HF after MI, and Dyrk1A inhibition may contribute to inactivation of this pathway and thereby retard the progression of MI-induced HF.
authors.affiliation: Institute of Cardiovascular Disease, Nantong University, Nantong, Jiangsu, People's Republic of China; Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Histology and Embryology, Nantong University, Nantong, Jiangsu, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.affiliation: Institute of Cardiovascular Disease, Nantong University, Nantong, Jiangsu, People's Republic of China; Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China. Electronic address: yjshz@ntu.edu.cn.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Institute of Cardiovascular Disease, Nantong University, Nantong, Jiangsu, People's Republic of China; Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China. Electronic address: zhujhntheart@163.com.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D000097603:Dyrk Kinases
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012313:RNA; D000097603:Dyrk Kinases
keywords: Heart failure; alternative splicing factor (ASF); calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ); dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)