The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy

Wang, Shudong; Ding, Lijuan; Ji, Honglei; Xu, Zheng; Liu, Quan; Zheng, Yang

doi:10.3390/ijms17071037

Cited by 73 publications

(54 citation statements)

References 106 publications

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“…Previous studies have shown a connection between DCM and the mitogen-activated protein kinase (MAPK) pathway (28), so we decided to examine whether HDAC3 inhibitor could block the activation of major MAPK family members: ERK1/2, JNK, and p38 MAPK. As shown in Fig 7 and Supplementary Fig 1, phosphorylated ERK1/2, JNK and p38 MAPK protein levels were significantly increased in the hearts of OVE26 diabetic mice compared with those of WT hearts at both 3 M and 6 M time points.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

et al. 2017

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Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevent DCM. Type 1 diabetes OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then sacrificed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice sacrificed immediately or 3 months later following the three-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two-time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. This study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.

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Section: Resultsmentioning

confidence: 99%

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

et al. 2017

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“…Although p38 inhibition is no longer under clinical investigation for RA, it has generated interest for a range of disorders involving dysregulated inflammation such as multiple sclerosis (62), chronic obstructive pulmonary disorder (COPD) (63), atherosclerosis (64, 65), diabetic cardiomyopathy (66), and neuropathic pain (67, 68). Our findings argue for careful analysis of the effects of p38 inhibitors on multiple potential compensatory pathways and on the background of multiple disease-relevant contexts to understand the full effects of drugs targeting p38 in inflammation-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

et al. 2018

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Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging, in part because of the complexities and interconnected nature of intracellular signaling networks, which complicate the effects of pharmacological interventions. Here, we characterized the signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. For example, p38 inhibitors, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NFκB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. CREB, a transcription factor that functions in part within a negative feedback loop in MAPK signaling, emerged as a key regulator of this context-dependence. CREB activation was induced predominately by p38 in response to inflammatory stimuli but by MEK in response to mitogenic stimuli; the effects of drugs targeting p38 or MEK were therefore markedly different in SFs cultured in mitogenic or inflammatory conditions. Together these findings illustrate how stimulatory context can alter pathway cross-talk even for a fixed network topology, suggest cross-talk by p38 in inflammatory contexts limited the benefit of p38 inhibitors in RA, and furthermore demonstrate the need for careful consideration of p38-targeted drugs in inflammation-related disorders.

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“…The mitogen‐activated protein kinase (MAPK) family which includes extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2), c‐Jun NH2‐terminal kinase (JNK), and p38MAPK plays an important role in the regulation of a large variety of cellular processes. MAPK activation is often necessary for cardiomyocyte hypertrophy, fibrosis, and apoptosis during hyperglycemia …”

Section: Introductionmentioning

confidence: 99%

The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways

Zhou

Sun

Zhang

et al. 2018

Diabetes Metabolism Res

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The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy

Cited by 73 publications

References 106 publications

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways

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