期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 40, 页码 27265-27272出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.022855
关键词
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资金
- National Institutes of Health [P01 HL085098, R01 HL066223, P01 HL48788, RR16434, T32HL07260, T32HL079995]
- The Riley Children's Foundation
The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1(-/-) mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1(+/+) mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca2+](i). Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of activity-dependent signal transduction leading to changes in gene expression.
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