Mixed Lineage Kinase 3 (MLK3) Prevents Cardiac Dysfunction and Structural Remodeling with Pressure Overload
Authors
Calamaras, Timothy DeanBaumgartner, Robert A.
Aronovitz, Mark J.
McLaughlin, Angela L.
Tam, Kelly
Richards, Daniel A.
Cooper, Craig W.
Li, Nathan
Baur, Wendy E.
Qiao, Xiaoying
Wang, Guang-Rong
Davis, Roger J.
Kapur, Navin Kumar
Karas, Richard H.
Blanton, Robert Morris Jr.
Document Type
Journal ArticlePublication Date
2018-10-26Keywords
Cardiac HypertrophyCardiomyocyte Hypertrophy
Heart Failure
Mixed Lineage Kinase
c-Jun N-terminal Kinase
Biochemistry
Cardiovascular Diseases
Cell Biology
Cellular and Molecular Physiology
Enzymes and Coenzymes
Molecular Biology
Metadata
Show full item recordAbstract
BACKGROUND: Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun N-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. METHODS AND RESULTS: We investigated Mixed Lineage Kinase 3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process has not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3(-/-)) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3-/- mice subjected to chronic LV pressure overload (TAC, four weeks) developed worsened cardiac dysfunction and increased LV chamber size compared to MLK3(+/+) littermates (n=8). LV mass, pathological markers of hypertrophy (Nppa, Nppb), and cardiomyocyte size were elevated in MLK3(-/-) TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3(-/-) TAC hearts. In adult rat cardiomyocytes pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. CONCLUSIONS: These data demonstrate MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF.Source
Am J Physiol Heart Circ Physiol. 2018 Oct 26. doi: 10.1152/ajpheart.00029.2018. [Epub ahead of print] Link to article on publisher's site
DOI
10.1152/ajpheart.00029.2018Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44492PubMed ID
30362822Related Resources
ae974a485f413a2113503eed53cd6c53
10.1152/ajpheart.00029.2018