title: Suppression of endothelin-1-induced cardiac myocyte hypertrophy by PPAR agonists: role of diacylglycerol kinase zeta.
abstract: OBJECTIVE
  Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiomyocyte hypertrophy, but the underlying signalling mechanisms remain unknown. We previously reported that the anti-hypertrophic effect of the dietary polyunsaturated fatty acid, conjugated linoleic acid (CLA), was associated with the upregulation of diacylglycerol (DAG) kinase (DGK). DGK catalyses phosphorylative conversion/attenuation of DAG, thereby modulating protein kinase C (PKC) and G-protein signalling. As the anti-hypertrophic effects of CLA were attenuated by inhibitors of PPARs, the present aim was to investigate the involvement of DGK in the anti-hypertrophic actions of bona fide selective PPAR agonists.
  
  
  RESULTS
  Endothelin-1 (ET1)-induced hypertrophy of neonatal, and then adult, Sprague-Dawley rat cardiomyocytes served as experimental paradigms. Expression of DGKζ, the predominant DGK isoform in myocytes, was stimulated by ligands of PPARγ (troglitazone) or PPARα (fenofibrate) and was accompanied by increased DGK activity. Troglitazone or fenofibrate prevented hypertrophic indicators elicited by ET1, including myocyte size augmentation, de novo protein synthesis, hypertrophic gene expression, and activation of the pro-hypertrophic signal, PKCε. shRNA knockdown of DGKζ abolished the growth-inhibitory effects of PPARs and restored all ET1-induced aspects of hypertrophy. Importantly, the involvement of DGK in the ability of troglitazone and fenofibrate to block ET1-induced hypertrophy and PKCε signalling was verified in adult rat myocytes.
  
  
  CONCLUSIONS
  Collectively, these findings show that the anti-hypertrophic actions of PPARs require DGKζ. Thus, within the cardiomyocyte, there exists a PPAR-DGK signalling axis that underpins the ability of PPAR ligands to inhibit ET1-dependent hypertrophy.
authors.affiliation: Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface General Hospital Research Centre, Manitoba, Canada.
authors.forename: Yingsu
authors.initials: Y
authors.lastname: Huang
authors.forename: Haining
authors.initials: H
authors.lastname: Zhang
authors.forename: Zongjun
authors.initials: Z
authors.lastname: Shao
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: O'Hara
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Kopilas
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Thomas
authors.initials: T
authors.lastname: Netticadan
authors.forename: Hope D
authors.initials: HD
authors.lastname: Anderson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002839:Chromans; D019332:Endothelin-1; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D019852:Diacylglycerol Kinase; C508008:diacylglycerol kinase zeta, rat; D000077288:Troglitazone; D011345:Fenofibrate