title: Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch.
abstract: Activation of members of the mitogen-activated protein (MAP) kinase family and their downstream effectors has been proposed to play a key role in the pathogenesis of cell survival, ischaemic preconditioning, cardiac hypertrophy and heart failure. This study investigated the responses of Src kinase and multiple MAP kinases during the transition from compensated pressure-overload hypertrophy to decompensated congestive heart failure. Extracellular signal-regulated protein kinase (ERK) 1/2, p38, and Src were activated by chronic pressure-overload and their activity was sustained for 8 weeks after aortic banding. In contrast, while p90 ribosomal S6 kinase (90RSK) and big MAP kinase 1 (BMK1) were activated in compensated hypertrophy, their activities were significantly decreased in hearts with heart failure. No changes were found in C-Jun NH2 terminal kinase (JNK) activity after aortic banding. These data suggest that differential activation of MAP kinase family members may contribute to the transition from compensated to decompensated hypertrophy. We also examined acute effects of mechanical stretch on the activation of these kinases in normal and hypertrophied hearts. In the isolated coronary-perfused heart, a balloon in the left ventricle was inflated to achieve minimum end-diastolic pressure of 25 mmHg for 10-20 min. In normal guinea pig hearts, stretch activated ERK1/2, p90RSK, p38, Src, and BMK1 but not JNK. However in hypertrophied hearts, further activation of these kinases was not observed by acute mechanical stretch. Mechanical stretch-induced activation of ERK1/2 and p38 kinase in normal hearts was attenuated significantly by a protein kinase C inhibitor, chelerythrine. We demonstrate that ERK1/2, p90RSK, p38, Src, and BMK1 are activated by chronic pressure-overload and by acute mechanical stretch. These data suggest that Src, BMK1 and p90RSK play a role as novel signal transduction pathways leading to cardiac hypertrophy. In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these two kinases to maintain cardiac function under chronic pressure-overload.
authors.forename: Y
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Glassman
authors.forename: W
authors.initials: W
authors.lastname: Che
authors.forename: J D
authors.initials: JD
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Kawakatsu
authors.forename: E G
authors.initials: EG
authors.lastname: Lawrence
authors.forename: B D
authors.initials: BD
authors.lastname: Hoit
authors.forename: B C
authors.initials: BC
authors.lastname: Berk
authors.forename: R A
authors.initials: RA
authors.lastname: Walsh
mesh_terms: D000470:Alkaloids; D000818:Animals; D001011:Aorta / Q000601:surgery; D053119:Benzophenanthridines; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D010617:Phenanthridines / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C016299:chelerythrine; D019061:src-Family Kinases; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases