Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH -terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulati...

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Published in:	American journal of physiology. Heart and circulatory physiology 2019-01, Vol.316 (1), p.H145-H159
Main Authors:	Calamaras, Timothy D, Baumgartner, 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 K, Karas, Richard H, Blanton, Robert M
Format:	Article
Language:	eng
Subjects:	Animals Aorta Cardiac Output Cardiomegaly - metabolism Cardiomegaly - pathology Cardiomegaly - physiopathology Cardiomyocytes Cardiomyopathy Cardiovascular disease Cells, Cultured Congestive heart failure Gene deletion Heart Humans Hypertrophy Kinases Male MAP kinase MAP kinase kinase MAP Kinase Kinase 4 - metabolism MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - genetics MAP Kinase Kinase Kinases - metabolism MAP Kinase Signaling System Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinase Kinase Kinase 11 Myocardium Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - physiology Oxidants Oxidizing agents Pharmacology Phosphorylation Pressure Protein Kinase Inhibitors - pharmacology Proteins Pyridines - pharmacology Pyrroles - pharmacology Rats Rats, Sprague-Dawley Regulators Risk analysis Risk factors Rodents Transcription factors Ventricle Ventricular Remodeling
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Summary:	Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH -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. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had 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 left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with 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. These data demonstrate that 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. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.
ISSN:	0363-6135 1522-1539