Camkiiδb mediates aberrant NCX1 expression and the imbalance of NCX1/SERCA in transverse aortic Constriction-Induced failing heart

Ying Mei Lu, Jiyun Huang, Norifumi Shioda, Kohji Fukunaga, Yasufumi Shirasaki, Xiao ming Li, Feng Han

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Ca 2+/calmodulin-dependent protein kinase II δB (CaMKIIδB) is one of the predominant isoforms of CaMKII in the heart. The precise role of CaMKIIδB in the transcriptional cross-talk of Ca 2+-handling proteins during heart failure remains unclear. In this work, we aim to determine the mechanism of CaMKIIδB in modulating the expression of sarcolemmal Na +-Ca 2+ exchange (NCX1). We also aim to address the potential effects of calmodulin antagonism on the imbalance of NCX1 and sarcoendoplasmic reticulum Ca 2+ ATPase (SERCA) during heart failure. Eight weeks after transverse aortic constriction (TAC)-induced heart failure in mice, we found that the heart weight/tibia length (HW/TL) ratio and the lung weight/body weight (LW/BW) ratio increased by 59% and 133%, respectively. We further found that the left ventricle-shortening fraction decreased by 40% compared with the sham-operated controls. Immunoblotting revealed that the phosphorylation of CaMKIIδB significantly increased 8 weeks after TAC-induced heart failure. NCX1 protein levels were also elevated, whereas SERCA2 protein levels decreased in the same animal model. Moreover, transfection of active CaMKIIδB significantly increased NCX1 protein levels in adult mouse cardiomyocytes via class IIa histone deacetylase (HDAC)/myocyte enhancer factor-2 (MEF2)-dependent signaling. In addition, pharmacological inhibition of calmodulin/CaMKIIδB activity improved cardiac function in TAC mice, which partially normalized the imbalance between NCX1 and SERCA2. These data identify NCX1 as a cellular target for CaMKIIδB. We also suggest that the CaMKIIδB-induced imbalance between NCX1 and SERCA2 is partially responsible for the disturbance of intracellular Ca 2+ homeostasis and the pathological process of heart failure.

Original languageEnglish
Article numbere24724
JournalPloS one
Volume6
Issue number9
DOIs
Publication statusPublished - 2011 Sep 13

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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