Premium
Digitalis‐induced activation of the sodium pump‐linked survival pathways in cardiac myocytes
Author(s) -
Liu Lijun,
Askari Amir
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.a234-d
Subject(s) - myocyte , ouabain , wortmannin , cardiac myocyte , pi3k/akt/mtor pathway , protein kinase b , medicine , digitalis , muscle hypertrophy , endocrinology , kinase , chemistry , phosphoinositide 3 kinase , microbiology and biotechnology , signal transduction , biology , sodium , heart failure , organic chemistry
Partial inhibition of cardiac Na + /K + ‐ATPase (sodium pump) by nontoxic concentrations of ouabain and related digitalis drugs is known to cause transactivation of Src/EGFR, activation of Ras/Raf/MEK/ERK1/2 cascade, transcriptional regulation of growth‐related genes, and myocyte hypertrophy.( L. Liu et al, AJP, 284, C1560, 2003; and Refs therein). To explore the nature of this drug‐induced growth, we have used cultured neonatal and adult rat cardiac myocytes, and examined the possibility of other specific kinases as downstream effectors of digitalis interaction with Na + /K + ‐ATPase. Stress‐activated MAPKs, JNKs and P38 kinase, were not affected by myocyte exposure to nontoxic concentrations of ouabain. However, the PI3K/Akt cascade, and its downstream branches, were strongly activated by these ouabain concentrations; and this ouabain effect was blocked by PI3K inhibitors wortmannin and LY‐294002. The ouabain‐induced hypertrophy of the neonatal myocytes was also prevented by PI3K inhibitors. These finding suggest that in cardiac myocytes, the protein kinase signaling pathways regulated by digitalis are more similar to the survival pathways associated with physiological hypertrophy, rather than those involved in pathological hypertrophy. (Supported by NIH Grant HL‐36573)