p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart

Li, Manxiang; Georgakopoulos, Dimitrios; Lü, Gang; Hester, Lisa; Kass, David A.; Hasday, Jeffery D.; Wang, Yibin

doi:10.1161/01.cir.0000165117.71483.0c

Cited by 139 publications

(110 citation statements)

References 54 publications

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“…The diabetic milieu upregulates p38 activity by phosphorylation [10]. Furthermore, p38 activity is intensified by TNF-α in cultured cardiomyocytes, as a positive feedback loop [13]. The p38 inhibitor prevents this phosphorylation of the p38 MAPK in cardiac tissue, as shown in the current study (Fig.…”

Section: Cardiac Inflammationsupporting

confidence: 79%

“…Consistent with these findings, diastolic function was still impaired with increased cardiac stiffness and increased LVEDP in STZP38. These findings are unexpected, because it has been shown that p38 inhibition leads to reduced cardiac fibrosis in a transgenic mouse model with enhanced p38 activity [13] and reduces LV dilatation after myocardial infarction in rats [31].…”

Section: Cardiac Fibrosismentioning

confidence: 97%

“…2). A recently conducted study [13] on non-diabetic, transgenic, p38-overexpressing mice that develop impaired cardiac function and increased cytokine levels found that these mice show an improvement of LV function after p38 inhibition. The mice also showed a reduction in circulating cytokine levels, despite a further increase in cardiac cytokine levels.…”

Section: Cardiac Inflammationmentioning

confidence: 99%

“…the p38 MAPK, play a pivotal role in the development of heart failure, including diabetic cardiomyopathy [10]. Via its signalling cascade, the p38 MAPK modulates genes that regulate myocyte apoptosis, cellular hypertrophy, cardiac fibrosis, and cardiac cytokine-mediated inflammation [11][12][13]. Because the p38 MAPK is not only upregulated and phosphorylated by ischaemia [14], but also, for example, by angiotensin II [15], oxidative stress [16], and high glucose levels [10], inhibition of p38 MAPK could be a potent new therapeutic option for treatment of diabetic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

et al. 2006

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Aims/hypothesis We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy. Materials and methods Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-α, IL6, IL1-β, and TGF-β1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining.

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Section: Cardiac Inflammationsupporting

confidence: 79%

Section: Cardiac Fibrosismentioning

confidence: 97%

Section: Cardiac Inflammationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

et al. 2006

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“…24,25 Similar results are obtained by genetic ablation of the p38 route (reviewed in ref. 17) while genetic activation in mice of the p38 pathway causes elevated cardiac dysfunction 26 and early death. 27 These effects are apparently mediated by the selective regulation of many cardiac target genes by p38.…”

Section: The P38 Modulementioning

confidence: 99%

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Mayor¹,

Jurado-Pueyo²,

Campos³

et al. 2007

Cell Cycle

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MEKK4 regulates developmental EMT in the embryonic heart

Stevens

Parker

Vaillancourt

2006

Developmental Dynamics

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Congenital heart malformations occur at a rate of one per one hundred births and are considered the most frequent birth defects. This high incidence of cardiac defects underscores the complex developmental processes required to form the first functioning organ in mammals. The molecular cues which govern heart development are poorly defined and require an improved understanding in order to advance repair strategies for heart defects. The cytoplasmic MAP kinase kinase kinase, MEKK4, is a critical effector in cellular stress responses; however, the function of MEKK4 during embryonic development and cardiogenesis is not well understood. We have identified MEKK4 as a critical signaling molecule during cardiovascular development. We report the detection of MEKK4 transcripts to early myocardium, endocardium and to cardiac cushion cells that have executed epithelial to mesenchymal transformation (EMT). These observations suggest that MEKK4 may function during production of the cushion mesenchyme as required to create valves and the septated heart. We used a kinase inactive form of MEKK4 (MEKK4 KI ) in an in vitro assay that recapitulates in vivo EMT, and show that MEKK4 KI attenuates mesenchyme production. However, addition of a constitutively active MEKK4 into ventricular explants, a system that does not normally undergo EMT, is not able to cause mesenchymal cell outgrowth. Thus, the kinase activity of MEKK4 is essential, but not sufficient, to support developmental EMT. This knowledge provides a basis to understand how MEKK4 may integrate signaling cascades controlling heart development.

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p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart

Cited by 139 publications

References 54 publications

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

MEKK4 regulates developmental EMT in the embryonic heart

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