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Right arrow Myocardial protection

Ann Thorac Surg 2005;80:2235-2241
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

p38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart

Meijing Wang, MD a , c , Ben M. Tsai, MD a , Mark W. Turrentine, MD a , Yousuf Mahomed, MD a , John W. Brown, MD a , Daniel R. Meldrum, MD a , b , c , *

a Section of Cardiothoracic Surgery, Departments of Surgery, Indianapolis, Indiana, USA
b Cellular and Integrative Physiology, Indianapolis, Indiana, USA
c Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

Accepted for publication May 19, 2005.

* Address correspondence to Dr Meldrum, 545 Barnhill Dr, Emerson Hall 215, Indianapolis, IN46202 (Email: dmeldrum{at}iupui.edu).

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-1ß 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-1ß 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-1ß 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-1ß, 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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