Involvement of a p38 Mitogen-activated Protein Kinase Phosphatase in Protecting Neonatal Rat Cardiac Myocytes from Ischemia

Mackay, Katrina; Mochly‐Rosen, Daria

doi:10.1006/jmcc.2000.1194

Cited by 48 publications

(28 citation statements)

References 14 publications

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“…Evidence is rapidly accumulating in support of a pathogenic role for p38 MAP kinase in myocardial dysfunction in animal models and humans (8,28). p38 MAP kinase activation has been implicated in ischemia, hypertrophy, apoptosis, and adrenergic signaling in cardiac myocytes (31,32,35,36,45,46). We now provide compelling evidence implicating p38 MAP kinase activation in the negative inotropic effect of gp120 in ARVM.…”

Section: Discussionmentioning

confidence: 64%

“…The time course of p38 MAP kinase activation (but not p44/42 or JNK) corresponds to the negative inotropic effect of HIV gp120. Activation of p38 MAP kinase appears to be an important component of the pathways activated by ischemia in cardiac myocytes (31,32,35,36). Thus the significance of this HIV gp120 signaling pathway in ARVM may extend beyond its potential relevance to HIV cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“…These effects appear to involve changes in intracellular ionized free calcium and p38 MAP kinase activation (13,19,24,34). Altered calcium homeostasis and p38 MAP kinase activation have also been implicated in myocardial dysfunction (8,21,27,31,32,35,36,40,46). We previously reported (23) that HIV gp120 stimulates p38 MAP kinase activation in neonatal rat cardiac myocytes.…”

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confidence: 95%

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p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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Kan, Hong, Zirong Xie, and Mitchell S. Finkel. p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. Am J Physiol Cell Physiol 286: C1-C7, 2004; 10.1152/ ajpcell.00059.2003.-Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca 2ϩ concentration ([Ca 2ϩ ]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca 2ϩ ]i within 5 min and then depressed FS without a decrease in [Ca 2ϩ ]i by 20-60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 M) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 M) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 M) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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confidence: 95%

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p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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“…On the one hand, p38 MAPK is well known to play a proapoptotic role in several cell types (16,19), whereas, on the other hand, studies also indicate that activation of p38 MAPK may have an antiapoptotic effect (13). This discrepancy in the role of p38 MAPK may be partly explained by the difference in experimental models, the presence of multiple p38 MAPK isoforms (p38␣, p38␤, p38␥, and p38␦), and the existence of several upstream MAPK kinases (MKKs), e.g., MKK3 and MKK6, which activate p38 MAPK.…”

Section: Translational Physiologymentioning

confidence: 99%

Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK

Watanabe

Ma²,

Hirabayashi³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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It is generally believed that a mechanical signal initiates a cascade of biological events leading to coordinated cardiac remodeling. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. To evaluate the molecular mechanism underlying swimming stress-induced cardiac remodeling, we examined the role of 14-3-3 protein and MAPK pathway by pharmacological and genetic means using transgenic mice with cardiac-specific expression of dominant-negative (DN) mutants of 14-3-3 (DN 14-3-3/TG) and p38α/β MAPK (DNp38α and DNp38β) mice. p38 MAPK activation was earlier, more marked, and longer in the myocardium of the TG group compared with that of the nontransgenic (NTG) group after swimming stress, whereas JNK activation was detected on day 5 and decreased afterward. In contrast, ERK1/2 was not activated after swimming stress in either group. Cardiomyocyte apoptosis, cardiac hypertrophy, and fibrosis were greatly increased in the TG group compared with those in the NTG group. Moreover, we found a significant correlation between p38 MAPK activation and apoptosis in the TG group. Furthermore, DN 14-3-3 hearts showed enhanced atrial natriuretic peptide expression. In contrast, DNp38α and DNp38β mice exhibited reduced mortality and increased resistance to cardiac remodeling after 28 days of swimming stress compared with TG and NTG mice. Besides, treatment with a p38 MAPK inhibitor, FR-167653, resulted in regression of cardiac hypertrophy and fibrosis and improvement in the survival rate in the TG group. These results indicate for the first time that 14-3-3 protein along with p38 MAPK plays a crucial role in left ventricular remodeling associated with swimming stress.

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“…However, some caution must be exercised in interpretation of these results with regard to the effects of vanadate on I/R hearts, inasmuch as vanadate has been shown to increase lactate dehydrogenase release, an index of cell death (4), in ischemic neonatal rat cardiomyocytes and increase their susceptibility to cell death by blocking tyrosine phosphatases and preventing inactivation of p38 mitogen-activated protein kinases (16). Moreover, the antioxidant activity of vanadate is questioned by the observation that vanadate has been shown to cause production of free radicals (13), with subsequent activation of transcriptional activation protein-1 in mouse epidermal JB6Pϩ cells, and these alterations were prevented by antioxidants such as N-acetylcysteine, as well as SOD ϩ CAT (8).…”

Section: Discussionmentioning

confidence: 99%

Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts

Takeda

Mochizuki²,

Saini³

et al. 2005

Journal of Applied Physiology

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. Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemicreperfused rat hearts. J Appl Physiol 99: 999 -1005, 2005. First published May 5, 2005; doi:10.1152/japplphysiol.00234.2005.-To study the cardioprotective effects of vanadate on ischemia-reperfusion (I/R) injury, isolated rat hearts perfused at constant flow were subjected to global ischemia for 30 min followed by reperfusion for 30 min. In this experimental model, I/R markedly decreased ventricular developed pressure and increased end-diastolic pressure. Pretreatment of hearts with 4 M vanadate attenuated I/R-induced cardiac dysfunction. The reduction in sarcoplasmic reticulum (SR) Ca 2ϩ uptake and Ca 2ϩ release, as well as SR protein contents for Ca 2ϩ -pump ATPase and Ca 2ϩ -release channel, was also prevented by vanadate. Pretreatment of hearts with an antioxidant mixture containing superoxide dismutase ϩ catalase exerted effects similar to those of vanadate in I/R hearts. Postischemic treatment of hearts with vanadate or superoxide dismutase ϩ catalase also had beneficial effects on I/R-induced changes in cardiac performance and SR function. Alterations in cardiac function and SR Ca 2ϩ transport due to an oxyradical-generating system (xanthine ϩ xanthine oxidase) or an oxidant (H2O2) were attenuated by treatment with vanadate. These results suggest that vanadate may exert beneficial effects on cardiac performance and SR function in I/R hearts because of its antioxidant action.ischemia-reperfusion; oxidative stress VANADATE HAS BEEN OBSERVED to produce beneficial effects on cardiac function in chronic diabetes (12,20,22). This action of vanadate on diabetic heart has been mainly attributed to its insulinomimetic property of promoting glucose uptake and oxidation in the cell (10, 27, 33) as a consequence of tyrosine kinase stimulation and/or inhibition of phosphotyrosine phosphatase activities (5, 34). Because diabetic cardiomyopathy has also been associated with oxidative stress (7), it is likely that attenuation of cardiac dysfunction in diabetes by vanadate may also be related to its antioxidant activity (17, 25). Although vanadate has been shown to scavenge oxyradicals generated by the xanthine plus xanthine oxidase (X ϩ XO) system (17), the antioxidant effect of vanadate remains to be clearly demonstrated. However, in a rat model of myocardial infarction, in which oxidative stress plays a critical role (19), the cytoprotective effect of vanadate has been shown to be associated with improvement in cardiac function, activation of phosphatidylinositol 3-kinase/protein kinase B (Akt), and inhibition of apoptosis by prevention of caspase-3 activation (30).Recently, vanadate at low concentrations (1-4 M) was found to attenuate cardiac dysfunction and changes in sarcoplasmic reticulum (SR) Ca 2ϩ uptake and ryanodine receptor (RyR)-binding activities due to ischemia-reperfusion (I/R) in isolated rat hearts (29). However, the results showing the beneficial actions of vanadate in this study (29) were not conclusive,...

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Involvement of a p38 Mitogen-activated Protein Kinase Phosphatase in Protecting Neonatal Rat Cardiac Myocytes from Ischemia

Cited by 48 publications

References 14 publications

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK

Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts

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