Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster

Kyoi, Shiori; Otani, Hajime; Matsuhisa, Seiji; Akita, Yuzo; Tatsumi, Kimiko; Enoki, Chiharu; Fujiwara, Hiroyoshi; Imamura, Hiroji; Kamihata, Hiroshi; Iwasaka, Toshiji

doi:10.1016/j.cardiores.2005.11.015

Cited by 65 publications

(60 citation statements)

References 30 publications

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“…In the infarct heart, cytokines such as tumor necrosis factor and interleukin 6 and injury of ischemia‐reperfusion activate the p38 signaling pathway 26. Furthermore, as a critical part of the response to MI in the heart, several investigations have confirmed that the p38 pathway sensitizes the caspase cascade to induce cell apoptosis, which supports our findings 27, 28. We observed that the activation of p38 was attenuated by knockdown of TGFβR3 under H 2 O 2 or MI conditions.…”

Section: Discussionsupporting

confidence: 88%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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BackgroundMyocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor‐β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.Methods and ResultsAn MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen‐activated protein kinase signaling were assessed by methylthiazolyldiphenyl‐tetrazolium bromide assay, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFβR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFβR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFβR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFβR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFβR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFβR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFβR3 by adeno‐associated viral vector serotype 9–TGFβR3 short hairpin RNA attenuated the effects of MI in mice.Conclusions TGFβR3 promotes apoptosis of cardiomyocytes via a p38 pathway–associated mechanism, and loss of TGFβR3 reduces MI injury, which suggests that TGFβR3 may serve as a novel therapeutic target for MI.

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Section: Discussionsupporting

confidence: 88%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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“…Deletion of JNK1 in the heart exacerbates fibrosis upon pressure overload (27). Chronic treatment with a JNK inhibitor, SP600125, increases apoptosis in cardiomyocytes and interstitial fibrosis in a hamster model of cardiomyopathy (28). In line with these findings, the suppression of JNK by miR-433 or siRNA was shown to trigger CF in the present study.…”

supporting

confidence: 84%

Cardiac fibrosis and miR-433

Oh¹,

Hajjar²,

Park³

2016

Ann. Transl. Med.

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“…Thus pharmacologic inhibition of JNK or p38 as a treatment for human heart disease would be more complicated if these animal studies directly translate (Figure 2). However, hamsters with muscular dystrophy and associated heart disease show less fibrosis and better cardiac function with systemic p38 MAPK inhibitor treatment, though a JNK inhibitor has no effect (114). Similar cardioprotection has also been observed in diabetic mice treated with a p38 MAPK inhibitor (115) and in mice following myocardial infarction injury (116).…”

Section: Mapk Inhibitionmentioning

confidence: 76%

Signaling effectors underlying pathologic growth and remodeling of the heart

2013

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Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

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Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster

Abstract: These results suggest that chronic treatment with p38 MAPK and JNK inhibitors produces opposing effects on the development of heart failure in the DCM hamster heart.

Cited by 65 publications

References 30 publications

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Cardiac fibrosis and miR-433

Signaling effectors underlying pathologic growth and remodeling of the heart

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