title: Dominant-negative p38alpha mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus.
abstract: The p38 mitogen-activated protein kinase (MAPK) is activated during heart diseases that might be associated with myocardial damage and cardiac remodeling process. Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. The purpose of this study was to investigate the role of p38alpha MAPK after experimental diabetes by using transgenic (TG) mice with cardiac-specific expression of a dominant-negative mutant form of p38alpha MAPK. The elevation of blood glucose was comparable between the nontransgenic (NTG) and TG mice. The expression of phospho-p38 MAPK and phospho-MAPK-activated protein kinase 2 levels were significantly suppressed in TG mice heart than in NTG mice after diabetes induction. Left ventricular (LV) dimension in systole was smaller, and the percent fractional shortening was higher in diabetic TG mice compared with diabetic NTG mice. In addition, diabetic TG mice had reduced cardiac myocyte diameter, content of cardiac fibrosis, LV tissue expressions of atrial natriuretic peptide, transforming growth factor beta1, and collagen III compared with diabetic NTG mice. Moreover, LV expression of NADPH oxidase subunits, p22(phox), p67(phox), gp91(phox), and Nox4, reactive oxygen species and lipid peroxidation levels were significantly increased in diabetic NTG mice, but not in diabetic TG mice. Furthermore, myocardial apoptosis, the number of caspase-3-positive cells, and the downregulation of antiapoptotic protein Bcl-X(L) were less in diabetic TG mice compared with diabetic NTG mice. In conclusion, our data establish that p38alpha MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38alpha MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-X(L).
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima Akiha-ku, Niigata 956-8603, Japan.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Meilei
authors.initials: M
authors.lastname: Ma
authors.forename: Narasimman
authors.initials: N
authors.lastname: Gurusamy
authors.forename: Punniyakoti T
authors.initials: PT
authors.lastname: Veeraveedu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Konishi
authors.forename: Shaosong
authors.initials: S
authors.lastname: Zhang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001835:Body Weight; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D005355:Fibrosis; D005799:Genes, Dominant; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D053148:Caspase 3; D047908:Intracellular Signaling Peptides and Proteins; D048308:Mitogen-Activated Protein Kinase 14; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D000099190:MAP-Kinase-Activated Kinase 2; C494812:Bcl2l1 protein, mouse; C505409:Casp3 protein, mouse