Cell type-specific angiotensin II-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts.
Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal-regulated kinases (ERKs). Ang II-induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the Gbetagamma subunit-binding domain of the beta-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II-induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II-induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II-induced ERK activation in cardiac myocytes. These findings suggest that Ang II-evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the Gbetagamma subunit of Gi protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas Gq and protein kinase C are important in cardiac myocytes.
Zou
Y
Y
Department of Medicine III, University of Tokyo School of Medicine, Japan.
Komuro
I
I
Yamazaki
T
T
Kudoh
S
S
Aikawa
R
R
Zhu
W
W
Shiojima
I
I
Hiroi
Y
Y
Tobe
K
K
Kadowaki
T
T
Yazaki
Y
Y
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D016391:Genes, src / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D005810:Multigene Family / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D018909:src Homology Domains / Q000502:physiology; D019061:src-Family Kinases
D011945:Receptors, Angiotensin; D000804:Angiotensin II; D004247:DNA; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins