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p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart.
Ann Thorac Surg 2005; 80(6):2235-41AT

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-1beta and interleukin-6 production.

METHODS

Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20 microM 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-1beta 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-1beta 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-1beta, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

Authors+Show Affiliations

Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16305880

Citation

Wang, Meijing, et al. "P38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart." The Annals of Thoracic Surgery, vol. 80, no. 6, 2005, pp. 2235-41.
Wang M, Tsai BM, Turrentine MW, et al. P38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart. Ann Thorac Surg. 2005;80(6):2235-41.
Wang, M., Tsai, B. M., Turrentine, M. W., Mahomed, Y., Brown, J. W., & Meldrum, D. R. (2005). P38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart. The Annals of Thoracic Surgery, 80(6), pp. 2235-41.
Wang M, et al. P38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart. Ann Thorac Surg. 2005;80(6):2235-41. PubMed PMID: 16305880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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 W, AU - Mahomed,Yousuf, AU - Brown,John W, AU - Meldrum,Daniel R, PY - 2005/03/16/received PY - 2005/05/17/revised PY - 2005/05/19/accepted PY - 2005/11/25/pubmed PY - 2005/12/31/medline PY - 2005/11/25/entrez SP - 2235 EP - 41 JF - The Annals of thoracic surgery JO - Ann. Thorac. Surg. VL - 80 IS - 6 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-1beta and interleukin-6 production. METHODS: Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20 microM 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-1beta 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-1beta 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-1beta, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection. SN - 1552-6259 UR - https://www.unboundmedicine.com/medline/citation/16305880/p38_mitogen_activated_protein_kinase_mediates_both_death_signaling_and_functional_depression_in_the_heart_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003-4975(05)00966-5 DB - PRIME DP - Unbound Medicine ER -