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Regulation of Connexin43 by NHE1 in Phenylephrine‐Induced Cardiomyocyte Hypertrophy
Author(s) -
Stanbouly Seta,
Kirshenbaum Lorrie,
Jones Doug,
Karmazyn Morris
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a692-a
Subject(s) - downregulation and upregulation , phenylephrine , muscle hypertrophy , connexin , myocyte , chemistry , medicine , gap junction , endocrinology , heart failure , intracellular , endogeny , microbiology and biotechnology , biology , biochemistry , gene , blood pressure
Connexin 43, the major gap junction protein expressed in cardiac ventricular cells, undergoes changes in distribution and expression levels in cardiac diseases. The Na‐H exchanger (NHE1), a key mediator of hypertrophy and heart failure, is colocalized with Cx43 in cardiac cells. Neonatal rat myocytes were treated with phenylephrine (PE) for 24 hours to induce hypertrophy. Increased Cx43 expression observed with PE treatment (35 ± 6% compared to control) was further significantly augmented by the NHE1 inhibitor EMD87580 (75 ± 9 % compared to control). As assessed with confocal microscopy, the observed diffuse distribution of Cx43 in the presence of PE was partially reversed with the addition of EMD. EMD prevented PE induced hypertrophy and JNK1/2 activation whereas inhibition of JNK1/2 significantly increased PE‐induced upregulation of Cx43 protein levels (40 ± 10 % vs 80 ± 9% with JNK inhibition). Inhibition of reverse mode Na‐Ca exchange (NCX) with KB‐R7943 partially reversed JNK1/2 activation (95 ± 21% vs 45 ± 14% with KB) and augmented upregulation of Cx43 protein (25 ± 9% vs 100 ± 29% with KB) in the presence of PE. Our results demonstrate that NHE1 negatively regulates Cx43 protein expression via JNK1/2 in PE‐induced cardiomyocyte hypertrophy. Increased intracellular Ca levels due to reverse mode NCX may be the link between NHE1 and activation of JNK1/2. This work is funded by the HSFO Program in Heart Failure and CIHR.