title: Evidence that apoptotic signalling in hypertrophic cardiomyocytes is determined by mitochondrial pathways involving protein kinase Cδ.
abstract: 1. Cardiomyocyte apoptosis plays an important role in the transition from cardiac hypertrophy to heart failure. Hyper-trophic cardiomyocytes show an increased susceptibility to apoptotic stimuli, but the mechanisms remain unclear. 2. We hypothesized that activated protein kinase Cδ (PKCδ) associated with cardiomyocyte hypertrophy could move from the cytoplasm to mitochondria, and subsequently trigger the apoptotic signalling pathway. 3. Hypertrophy was induced in cultured neonatal rat cardiomyocytes using endothelin-1 (ET-1), insulin-like growth factor-1 (IGF-1), thyroid hormone (T(3) ) or angiotensin-II (AngII). AngII at high concentrations (1 and 10 nmol/L) also induced apoptosis. Hypertrophic cells were then treated with AngII with or without specific inhibitors of the angiotensin receptors AT(1) and AT(2) (losartan and PD123319, respectively), endothelin receptor A (BQ-123) and PKCδ (rottlerin). ET-1 plus AngII had a threefold and significant increase in apoptosis in the hypertrophic cultures compared with AngII alone. In association with the increase in apoptosis, this treatment also promoted mitochondrial translocation of PKCδ, and increased expression of cleaved caspase 9 and activity of caspase 3. All of these increases were modulated by concurrent use of the PKCδ inhibitor, rottlerin. 4. The results suggest that apoptotic signalling in hypertrophic cardiomyocytes is determined by mitochondrial pathways involving PKCδ.
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Man-Jiang
authors.initials: MJ
authors.lastname: Xie
authors.forename: Hui
authors.initials: H
authors.lastname: Chang
authors.forename: Yun-Ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Song
authors.forename: Wan-Gang
authors.initials: WG
authors.lastname: Guo
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Che
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Yu
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D053453:Caspase 9 / Q000096:biosynthesis; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D019332:Endothelin-1; D007093:Imidazoles; D010456:Peptides, Cyclic; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017466:Receptors, Endothelin; C548904:insulin-like growth factor-1, rat; D014284:Triiodothyronine; D000804:Angiotensin II; C073402:PD 123319; D007334:Insulin-Like Growth Factor I; C085746:rottlerin; D051745:Protein Kinase C-delta; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; C072247:cyclo(Trp-Asp-Pro-Val-Leu)