title: Phospholipase C/protein kinase C pathway mediates angiotensin II-dependent apoptosis in neonatal rat cardiac fibroblasts expressing AT1 receptor.
abstract: 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.
authors.affiliation: Centro FONDAP Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Chile.
authors.forename: Raul
authors.initials: R
authors.lastname: Vivar
authors.forename: Cristian
authors.initials: C
authors.lastname: Soto
authors.forename: Miguel
authors.initials: M
authors.lastname: Copaja
authors.forename: Francisca
authors.initials: F
authors.lastname: Mateluna
authors.forename: Pablo
authors.initials: P
authors.lastname: Aranguiz
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Muñoz
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: Lorena
authors.initials: L
authors.lastname: Garcia
authors.forename: Alan
authors.initials: A
authors.lastname: Letelier
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Díaz-Araya
mesh_terms: 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*
chemical_list: 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