title: Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats.
abstract: OBJECTIVE
  It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats.
  
  
  METHODS
  Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample.
  
  
  RESULTS
  Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB.
  
  
  CONCLUSIONS
  Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling.
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Nantong University, Nantong, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Qin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Sheng
mesh_terms: D017398:Alternative Splicing; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000188:drug therapy*; D004452:Echocardiography; D006973:Hypertension; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000068756:Valsartan / Q000494:pharmacology*; D000097603:Dyrk Kinases
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000068756:Valsartan; D000097603:Dyrk Kinases