title: Abnormal calcium and protein kinase C-epsilon signaling in hypertrophied atrial tumor myocytes (AT-1 cells).
abstract: Cardiac hypertrophy leads to contractile dysfunction and altered hormone responsiveness through incompletely understood mechanisms. Atrial tumor (AT-1) myocytes (AT-1 cells) are a cardiomyocyte lineage that proliferates but hypertrophies when proliferation is prevented with mitomycin C. Because both states maintain a highly differentiated phenotype, AT-1 cells were used to explore the signaling pathways that accompany and/or contribute to hypertrophic cardiomyocyte growth. Mitomycin C-induced AT-1 cell enlargement is associated with a pronounced increase in the amplitude and the duration of both electrically stimulated calcium transients and endothelin receptor-dependent calcium responses. Studies with caffeine indicate that the intracellular pool of releasable calcium is similar in control and hypertrophied AT-1 cells. This agrees with the results of Northern analyses that show similar steady-state levels of transcripts encoding the sarcoplasmic reticulum Ca-ATPase (and higher levels of transcripts encoding the Na+/Ca2+ exchanger) in hypertrophied AT-1 cells, relative to proliferating control cultures. However, immunoblot analyses reveal a marked increase in the expression of protein kinase C (PKC)-epsilon (a critical intermediate in the signaling pathway for endothelin receptor-dependent modulation of intracellular calcium) during AT-1 cell hypertrophy; the abundance of other PKC isoforms is not changed. Collectively, these results identify reciprocal regulation between calcium/PKC signaling and hypertrophic growth. The evidence that AT-1 cell hypertrophy leads to abnormalities in calcium regulation and specific changes in PKC-epsilon expression that alter endothelin receptor responsiveness supports the notion that pathophysiological changes in PKC-epsilon abundance lead to functionally important changes in hormonal modulation of cardiomyocyte function.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kline
authors.forename: T
authors.initials: T
authors.lastname: Jiang
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: V O
authors.initials: VO
authors.lastname: Rybin
authors.forename: S F
authors.initials: SF
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006338:Heart Neoplasms / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D016232:Endothelins; D007527:Isoenzymes; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D002110:Caffeine; D016685:Mitomycin; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases