The role of MEKK1 in hypertrophic cardiomyopathy.
MEKK1 is a ubiquitously expressed mitogen activated protein kinase that is involved in tissue remodeling in a variety of settings including carotid artery blood flow cessation, wound healing, and breast adenocarcinoma intravasation. Here, we have tested the function of MEKK1 in genetic hypertrophic cardiomyopathy (HCM). MEKK1 was genetically deleted in C57Bl6/J mice expressing a mutant alpha-myosin heavy chain (HCM-MEKK1(-/-)). The absence of MEKK1 in HCM resulted in a more pronounced hypertrophy when compared to HCM mice with the MEKK1 gene intact without further increases in atrial natriuretic factor and beta-myosin heavy chain (MyHC) expression and fibrosis. Since MEKK1 is required for the induction of several tissue proteases, we tested the hypothesis that cardiac enlargement of HCM- MEKK1(-/-) mice was due to altered expression of urokinase-type plasminogen activator (uPA), JunB, matrix-metalloproteinase (MMP), and tissue inhibitors of MMPs (TIMPs). Because of its role in preventing apoptosis, we also tested the loss of MEKK1 on apoptotic mediators Bcl-2, cytochrome C, caspase-9, and caspase-3. uPA expression was decreased while JunB, MMP-9, caspase-9, and caspase-3 activities were elevated in HCM- MEKK1(-/-) hearts when compared to MEKK1(-/-), wild-type (WT), and HCM mice. Bcl-2 and Cyt C expression was elevated only in HCM mice. We conclude that the absence of MEKK1 induces a more pronounced cardiac hypertrophy to HCM through altered expression of proteases implicated in cardiac remodeling and increased apoptosis.
Konhilas
John P
JP
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA.
Boucek
Dana M
DM
Horn
Todd R
TR
Johnson
Gary L
GL
Leinwand
Leslie A
LA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D024722:Cardiac Myosins / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D048728:MAP Kinase Kinase Kinase 1 / Q000502:physiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D048728:MAP Kinase Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains