title: Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading.
abstract: Background- Mechanical unloading of the heart with a left ventricular assist device (LVAD) leads to favorable changes in the biology of the failing cardiac myocyte. To determine a potential mechanism for these improvements, we examined the regulation of mitogen-activated protein kinases (MAPKs) in the failing heart in the presence and absence of LVAD support. Methods and Results- We examined the degree of activation (ie, phosphorylation) of p44/42 extracellularly regulated kinase, p38 kinase, and c-Jun N-terminal kinase (JNK1/2), and the corresponding activity levels of these MAPKs in myocardial samples obtained from 11 patients with LVAD support and in 11 patients without LVAD support. MAPK activity was also examined in an additional 6 patients from whom paired samples were obtained before and after LVAD support. The activity of p44/42 and JNK1/2 were reduced significantly, whereas p38 activity levels were significantly increased after LVAD support. We examined functional parameters that are linked to MAPK activation, namely cardiac myocyte hypertrophy and apoptosis. Both cardiac myocyte cell size and the incidence of cardiac myocyte apoptosis were significantly reduced after LVAD support. Conclusions- Mechanical unloading of the failing heart leads to differential regulation of MAPKs. These changes in MAPK activity are associated with changes in myocyte hypertrophy and viability, suggesting a potential mechanistic basis for some of the observed salutary changes after LVAD support.
authors.affiliation: Winters Center for Heart Failure Research, Baylor College of Medicine, VA Medical Center, Houston, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: K B
authors.initials: KB
authors.lastname: Margulies
authors.forename: H C
authors.initials: HC
authors.lastname: Mochmann
authors.forename: D
authors.initials: D
authors.lastname: Engel
authors.forename: N
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: D L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D048429:Cell Size; D002470:Cell Survival; D015331:Cohort Studies; D004789:Enzyme Activation; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases