Phospholipase C/protein kinase C pathway mediates angiotensin II-dependent apoptosis in neonatal rat cardiac fibroblasts expressing AT1 receptor.
Cardiac fibroblasts are the major non-myocyte cell constituent in the myocardium, and they are involved in heart remodeling. Angiotensin II type 1 receptor (AT1R) mediates the established actions of angiotensin II (Ang II), and changes in its expression have been reported in cardiac fibroblasts after myocardial infarction. However, the AT1R-dependent signaling pathways involved in cardiac fibroblast death remain unknown. Using adenovirus, we ectopically expressed AT1R in cultured neonatal rat cardiac fibroblasts and investigated the role of the phospholipase (PLC)/protein kinase C (PKC) pathway on Ang II-dependent death. Ang II induced cardiac fibroblast death characterized by an early loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, caspase-3 activation, and DNA fragmentation. All these effects were prevented by the AT1R antagonist losartan, PLC inhibitor U73122, and PKC inhibitor Gö6976. We conclude that Ang II stimulates the intrinsic apoptotic pathway in cultured cardiac fibroblasts by the AT1R/PLC/PKC signaling pathway.
Vivar
Raul
R
Centro FONDAP Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Chile.
Soto
Cristian
C
Copaja
Miguel
M
Mateluna
Francisca
F
Aranguiz
Pablo
P
Muñoz
Juan Pablo
JP
Chiong
Mario
M
Garcia
Lorena
L
Letelier
Alan
A
Thomas
Walter G
WG
Lavandero
Sergio
S
Díaz-Araya
Guillermo
G
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D004963:Estrenes / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D019808:Losartan / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D002227:Carbazoles; D004963:Estrenes; D011760:Pyrrolidinones; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C081021:Go 6976; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019808:Losartan