Mild doses of oxidative stress in the heart correlate with the induction of apoptosis or hypertrophy in cardiomyocytes (CMCs) and fibrosis or proliferation of fibroblasts. Three branches of mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinases (JNKs), extracellular signal-related kinases 1 and 2 (ERK1/2), and p38, are activated by oxidants in a variety of cell types, including CMCs. However, the initiation process of these signaling pathways remains unsolved. We explored the role of the epidermal growth factor (EGF) receptor in H2O2-induced MARK activation using two different cell types from the same organ: CMCs and heart fibroblasts (HFs). Pretreatment of each cell type with EGF revealed differences in how CMCs and HFs responded to subsequent treatment with H2O2: in CMCs, the second treatment resulted in little further activation of JNKs and ERK1/2, whereas HFs retained the full response of JNKs and ERK1/2 activation by H 2O2 regardless of EGF pretreatment. AG-1478 [4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline], a pharmacologic inhibitor of the EGF receptor tyrosine kinase, inhibited JNK and ERK1/2 activations but not p38 in both cell types. The data using the Src inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] resemble those found when using AG-1478 in either cell type. Pharmacologic inhibitors of matrix metalloproteinases (MMPs) further illustrated the difference between the two cell types. In HFs, MMP inhibitors GM6001 [N-[(2R)-2- (hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide] and BB2516 [[2S-[N4(R*),2R*,3S*]]-N4-[2,2-dimethyl-1- [(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methylpropyl)butanediamide, marimastat] inhibited JNKs and ERK1/2 activation without affecting p38 activation by H2O2. In contrast, these MMP inhibitors failed to significantly inhibit the activation of JNKs, ERKs, or p38 in CMCs. These data suggest the complexity of the cell type-dependent signaling web initiated by oxidants in the heart.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Mar 2005|
ASJC Scopus subject areas
- Molecular Medicine