Idioma:

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

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

American journal of physiology. Heart and circulatory physiology, 2019-01, Vol.316 (1), p.H145-H159 [Periódico revisado por pares]

United States: American Physiological Society

Texto completo disponível

Citações Citado por

Enviar para

Título:
Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload
Autor: 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
Assuntos: 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
É parte de: American journal of physiology. Heart and circulatory physiology, 2019-01, Vol.316 (1), p.H145-H159
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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.
Editor: United States: American Physiological Society
Idioma: Inglês

Links

View this record in MEDLINE/PubMed

Voltar para lista de resultados

Realização: Logos de Redes Sociais:

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

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

United States: American Physiological Society

Buscando em bases de dados remotas. Favor aguardar.