p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart

Meijing Wang, Ben M. Tsai, Mark Turrentine, Yousuf Mahomed, John Brown, Daniel R. Meldrum

Research output: Contribution to journalArticle

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Abstract

Background. Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1β and interleukin-6 production. Methods. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20μM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1β and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Results. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 ± 3.87 MKI versus 32.7 ± 4.32 mm Hg; +dP/dt: 1392.0 ± 141.7 MKI versus 896.7 ± 128.5 mm Hg/s; -dP/dt: -889.9 ± 97.63 MKI versus -548.9 ± 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 ± 4.59 MKI vs 69.95 ± 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1β and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. Conclusions. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1β, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

Original languageEnglish
Pages (from-to)2235-2241
Number of pages7
JournalAnnals of Thoracic Surgery
Volume80
Issue number6
DOIs
StatePublished - Dec 2005

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p38 Mitogen-Activated Protein Kinases
Caspase 1
Caspases
Interleukin-1
Tumor Necrosis Factor-alpha
Caspase 3
Interleukin-6
Ischemia
Ventricular Pressure
Mitogen-Activated Protein Kinases
Protein Kinases
Reperfusion
Apoptosis
Protein Kinase Inhibitors
Oxidants
Myocardial Ischemia
Blood Pressure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart. / Wang, Meijing; Tsai, Ben M.; Turrentine, Mark; Mahomed, Yousuf; Brown, John; Meldrum, Daniel R.

In: Annals of Thoracic Surgery, Vol. 80, No. 6, 12.2005, p. 2235-2241.

Research output: Contribution to journalArticle

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title = "p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart",
abstract = "Background. Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1β and interleukin-6 production. Methods. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20μM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1β and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Results. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 ± 3.87 MKI versus 32.7 ± 4.32 mm Hg; +dP/dt: 1392.0 ± 141.7 MKI versus 896.7 ± 128.5 mm Hg/s; -dP/dt: -889.9 ± 97.63 MKI versus -548.9 ± 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 ± 4.59 MKI vs 69.95 ± 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1β and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. Conclusions. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1β, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.",
author = "Meijing Wang and Tsai, {Ben M.} and Mark Turrentine and Yousuf Mahomed and John Brown and Meldrum, {Daniel R.}",
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T1 - p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart

AU - Wang, Meijing

AU - Tsai, Ben M.

AU - Turrentine, Mark

AU - Mahomed, Yousuf

AU - Brown, John

AU - Meldrum, Daniel R.

PY - 2005/12

Y1 - 2005/12

N2 - Background. Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1β and interleukin-6 production. Methods. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20μM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1β and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Results. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 ± 3.87 MKI versus 32.7 ± 4.32 mm Hg; +dP/dt: 1392.0 ± 141.7 MKI versus 896.7 ± 128.5 mm Hg/s; -dP/dt: -889.9 ± 97.63 MKI versus -548.9 ± 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 ± 4.59 MKI vs 69.95 ± 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1β and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. Conclusions. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1β, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

AB - Background. Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1β and interleukin-6 production. Methods. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20μM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1β and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Results. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 ± 3.87 MKI versus 32.7 ± 4.32 mm Hg; +dP/dt: 1392.0 ± 141.7 MKI versus 896.7 ± 128.5 mm Hg/s; -dP/dt: -889.9 ± 97.63 MKI versus -548.9 ± 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 ± 4.59 MKI vs 69.95 ± 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1β and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. Conclusions. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1β, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

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