Premium
Angiotensin II‐induced ERK1/2 activation is mediated by PKC delta and intracellular calcium in cardiac fibroblasts
Author(s) -
Shamhart Patricia,
Olson Erik,
Naugle Jennifer,
Doane Kathleen,
Meszaros J. Gary
Publication year - 2008
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.22.1_supplement.748.4
Subject(s) - protein kinase c , mapk/erk pathway , rottlerin , angiotensin ii , microbiology and biotechnology , chemistry , kinase , intracellular , signal transduction , downregulation and upregulation , calcium in biology , pharmacology , endocrinology , medicine , receptor , biology , biochemistry , gene
Activated cardiac fibroblasts (CFs) proliferate, differentiate, and migrate to regulate cardiac remodeling. ANG II activates extracellular signal‐regulated kinase (ERK) 1/2 to induce proliferation, but the signaling pathways leading to ERK 1/2 activation have not been elucidated in CFs. The goal of the current study was to identify the intracellular mediators of ANG II‐induced ERK 1/2 activation in adult rat CFs. We determined that ANG II does not transactivate the epidermal growth factor receptor (EGFR) in adult CFs, since pretreatment with AG 1478 did not inhibit [ 3 H]‐thymidine incorporation or ERK 1/2 activation. We found that ANG II‐induced ERK 1/2 phosphorylation is inhibited by simultaneous chelation of cytosolic Ca 2+ and downregulation of PKC by phorbol ester or by the specific PKC inhibitor rottlerin as well as PKC siRNA, but not by inhibition of each agent alone. We next investigated the role of specific PKC isoforms in migration of the activated CFs using in vitro wound healing assays. Through pharmacological blockade we determined that inhibition of PKC slows migration of CFs and inhibition of PKC also decreases the rate migration but to a lesser extent than blockade of PKC. These data reveal that PKC is a key mediator in both ANG II‐induced proliferation with concurrent Ca 2+ chelation and migration of CFs.