P38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart Meijing Wang, MD, Ben M. Tsai, MD, Mark W.

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p38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart Meijing Wang, MD, Ben M. Tsai, MD, Mark W. Turrentine, MD, Yousuf Mahomed, MD, John W. Brown, MD, Daniel R. Meldrum, MD The Annals of Thoracic Surgery Volume 80, Issue 6, Pages 2235-2241 (December 2005) DOI: 10.1016/j.athoracsur.2005.05.070 Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 The p38 mitogen-activated protein kinase (MAPK) signaling in inflammation and apoptosis. Acute ischemia-reperfusion, oxidant stress, and hydrogen peroxide directly activate p38 MAPK, which results in activation of downstream signal-mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2). Active p38 MPAK and MAPKAPK2 lead to tumor necrosis factor (TNF) gene induction. Nuclear factor kappa B (NFκB) is activated by inhibitory κB (IκB) phosphorylation and subsequently disruption of the NFκB-IκB complex. Activated NFκB translocates from the cytoplasm to the nucleus, where it docks to the TNF promoter and activates TNF gene transcription. Active p38 MAPK and MAPKAPK2 also result in production of interleukin-1 beta (IL-1β) by active/cleaved caspase-11 and caspase-1. The inflammatory response (p38 MAPK signaling, TNF, and IL-1β) and caspase-11 eventually lead to active caspase-3 and apoptosis. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Changes in myocardial function after ischemia and reperfusion in ischemia/reperfusion (I/R) alone (n = 14) and I/R + p38 mitogen-activated protein kinase inhibitor (MKI) (n = 19) rat hearts perfused with modified Krebs-Henseleit solution. (A) Left ventricular (LV) developed pressure. (B) Left ventricular end-diastolic pressure. (C) The +dP/dt. (D) The −dP/dt. Results are mean ± standard error of the mean. *p < 0.05. **p < 0.01. ***p < 0.001 versus I/R alone at the corresponding points. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 The expression of activated p38 mitogen-activated protein kinase (MAPK) signaling pathway is increased after ischemia/reperfusion (I/R) injury in I/R alone relative to I/R + p38 mitogen-activated protein kinase inhibitor (MKI). (A) Representative immunoblots show nonphosphorylated p38 MAPK (total) in the top row with phosphorylated p38 MAPK (active) in the bottom row. (B) Representative immunoblots show phosphorylated mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) (active). (C) Densitometry data of p-p38 MAPK (percentage of total p38 MAPK). (Mean ± standard error of the mean [n = 4 to 6/group].) *p < 0.001 versus control, ▿p < 0.05 versus I/R alone. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Ischemia-reperfusion (I/R)-induced production of (A) myocardial tumor necrosis factor (TNF), (B) interleukin-1 beta (IL-1β), and (C) interleukin-6 (IL-6) protein. Protein levels of myocardial TNF, IL-1β, and IL-6 were significantly increased by I/R, but p38 mitogen-activated protein kinase inhibitor decreased these myocardial cytokines compared with I/R alone. (Mean ± standard error of the mean [n = 4 to 5/group]). *p < 0.05 versus control; ▿p < 0.05 versus I/R alone. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Expression of caspase-1 and caspase-11 in control, ischemia-reperfusion (I/R) alone and I/R + p38 MKI rat hearts after I/R injury. (A) Shown are representative immunoblots of precursor procaspase-11 in the top row with active caspase-11 in the bottom row. (B) Shown are representative immunoblots of precursor procaspase-1 in the top row with active caspase-1 in the bottom row. (C) Densitometry data of caspase-11 (% of procaspase-11). The I/R increased expression of active caspase-11 levels. The increased caspase-11 activation after I/R was reduced by p38 mitogen-activated protein kinase inhibition (MKI). (D) Densitometry data of caspase-1 (% of procaspase-1). Active caspase-1 levels were increased after I/R. However, increased caspase-1 activation after I/R was reduced by p38 MAPK inhibition. (Mean ± standard error of the mean [n = 3 to 9/group]). *p < 0.05 versus control. ▿p < 0.05 versus I/R alone. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 6 Expression of active caspase-3 in ischemia-reperfusion (I/R) alone and I/R + p38 mitogen-activated protein kinase inhibitor (MKI) rat hearts. (A) Representative immunoblots of active caspase-3 (p20 and p17 subunits). (B) Densitometry data of active caspase-3 (p20 and p17) (% of caspase-3 p20, p17 in I/R alone group, respectively). (Mean ± standard error of the mean [n = 3/group].) *p < 0.05. **p < 0.001 versus I/R alone. The Annals of Thoracic Surgery 2005 80, 2235-2241DOI: (10.1016/j.athoracsur.2005.05.070) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions