Decreased p38 MAPK Activity in End-Stage Failing Human Myocardium: p38 MAPK α is the Predominant Isoform Expressed in Human Heart

Lemke, Leslie E.; Bloem, Laura J.; Fouts, Rebecca L.; Esterman, Michail A.; Sandusky, George E.; Vlahos, Chris J.

doi:10.1006/jmcc.2001.1415

Cited by 84 publications

(57 citation statements)

References 34 publications

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“…With respect to our transgenic strategies, the dnMKK3 and dnMKK6 mutant proteins should effectively reduce signaling through p38α, p38β (only for dnMKK6), p38γ, and p38δ, while the dnp38α should block signaling to those effectors that are in common between p38α, p38β, p38γ, and p38δ. With respect to expression, p38α, p38β, and p38γ, but not p38δ, have been detected in the myocardium, although p38α is thought to predominate (15,34,(36)(37)(38). At the protein level, we determined that p38β was barely detectable in the adult heart, somewhat consistent with the recent data from two other groups who reported essentially no p38β in the heart (15,38).…”

Section: Discussionsupporting

confidence: 90%

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Braz¹,

Bueno²,

Liang³

et al. 2003

J. Clin. Invest.

210

191

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Section: Discussionsupporting

confidence: 90%

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Braz¹,

Bueno²,

Liang³

et al. 2003

J. Clin. Invest.

210

191

View full text Add to dashboard Cite

“…The effects of MKK6 overexpression on mitogen-activated protein kinase activity were assessed focusing on p38␣ and -␤, the two major isoforms of this mitogen-activated protein kinase in the heart (22,32,33). Using isoform-specific antisera (Fig 2A), the relative levels of p38␣ and -␤ were determined in various mouse tissues.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Martindale

Wall

Martinez-Longoria

et al. 2005

Journal of Biological Chemistry

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The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, ␣B-crystallin (␣BC), in cultured cardiac myocytes, we examined ␣BC levels in the mouse hearts. The level of ␣BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in ␣BC levels in the mitochondrial fractions of TG mouse hearts but no increase in ␣BC levels in any of the other fractions analyzed. These alterations in ␣BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.

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“…With respect to expression, p38α, p38β, and p38γ, but not p38δ, have been detected in the myocardium, although p38α is thought to predominate (15,34,(36)(37)(38). At the protein level, we determined that p38β was barely detectable in the adult heart, somewhat consistent with the recent data from two other groups who reported essentially no p38β in the heart (15,38). We also generated dnp38β transgenic mice, but intriguingly, they failed to show inhibition of p38 activity likely due to unknown technical difficulties (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Braz¹,

Bueno²,

Liang³

et al. 2003

J. Clin. Invest.

268

View full text Add to dashboard Cite

The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38α, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38α, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38α directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38α transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Aβ gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling

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Decreased p38 MAPK Activity in End-Stage Failing Human Myocardium: p38 MAPK α is the Predominant Isoform Expressed in Human Heart

Cited by 84 publications

References 34 publications

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

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