The Role of MEKK1 in Hypertrophic Cardiomyopathy

Abstract

SummaryMEKK1 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 α-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 β-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. (Int Heart J 2010; 51: 277-284)

Cyclin D2 is a critical mediator of exercise-induced cardiac hypertrophy

“…32 In contrast, pathological cardiac hypertrophy and cardiac dysfunction were increased in these mice with pressure overload 31 and familial hypertrophic cardiomyopathy. 30 Here we demonstrate that expression of MEKK1 is not required for exercise capacity nor is it required for cardiac growth in response to the exercise stimulus. It appears, then, that although the role of MEKK1 in pathological hypertrophy may be stimulus-dependent, MEKK1 is not required for physiological hypertrophy.…”

“…Exercise performance and cardiac adaptation in MEKK1 À/À mice MEKK1 signaling has been demonstrated to both mediate Gaq-induced pathologic hypertrophy 32 and confer a protective role in cardiac disease. 30,31 Because of the opposing roles of MEKK1 in hypertrophy, we examined whether exercise performance and cardiac adaptation to exercise were affected in MEKK1 À/À female mice. Since MEKK1 À/À mice were bred to each other, there were no littermate controls.…”

“…[26][27][28][29] MAPK/ERK kinase (MEK) kinase-1 (MEKK1) signaling is also important for pathological hypertrophy and can play opposite roles in the development of pathological hypertrophy depending on the context. [30][31][32] Lastly, increases in the cell cycle regulators, including cyclin D2, are associated with pathological cardiac hypertrophy 33 and mice lacking cyclin D2 have attenuated pathological hypertrophy. 34,35 In order to determine whether these hypertrophic signaling molecules would impact the exercise response, we used a number of genetic mouse models to assess exercise performance and the hypertrophic response to exercise training.…”

TWEAK and NT‐proBNP levels predict exercise capacity in hypertrophic cardiomyopathy

“…The role of apoptosis in HCM has been deeply investigated. The remodelling of the heart is associated with a transition from a compensated hypertrophic state to a decompensated dilated heart, related to myocyte apoptosis . This apoptosis can lead to a wall thinning, which is common in HCM, and systolic function worsening .…”

Histone deacetylase HDAC4 participates in the pathological process of myocardial ischemia-reperfusion injury via MEKK1/JNK pathway by binding to miR-206

“…In addition, miR-206 is implicated in the regulation of skeletal muscle differentiation via suppression of multiple factors of the c-Jun N-terminal kinase (JNK)/mitogen-activated kinase-like protein (MAPK) pathway such as mitogen-activated protein kinase kinase kinase 1 (MEKK1) and MAP kinase kinase 7 [ 16 ], which is highly suggestive of a novel regulatory mechanism involving HDAC4, miR-206, and the MEKK1/JNK pathway. Meanwhile, MEKK1 is a protein kinase activated by mitogen and has been demonstrated to be implicated in cardiac remodeling [ 17 ]. JNK is a protein kinase that can be activated by stress or mitogen, and incorporation of the mitochondrial JNK pathway has been indicated in ischemic myocardial dysfunction [ 18 ].…”