title: Cardiac-specific overexpression of diacylglycerol kinase zeta attenuates left ventricular remodeling and improves survival after myocardial infarction.
abstract: Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGKzeta-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta1 (P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGKzeta-TG mice. The survival rate at 4 wk after MI was higher in DGKzeta-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGKzeta suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKzeta may be a potential novel therapeutic target to prevent LV remodeling after MI.
authors.affiliation: Department of Cardiology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Japan 990-9585.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niizeki
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Takanori
authors.initials: T
authors.lastname: Arimoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Yo
authors.initials: Y
authors.lastname: Koyama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.forename: Richard A
authors.initials: RA
authors.lastname: Walsh
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005355:Fibrosis; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D011493:Protein Kinase C; D018995:Myosin Heavy Chains