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Dr Thomas Krieg

Dr Thomas Krieg

University Lecturer in Clinical Pharmacology

Honorary Consultant Physician


Office Phone: 01223 762584

Research Interests

Cardiovascular Ischaemia/Reperfusion Injury

A heart attack occurs when a blood clot forms in a coronary artery depriving blood flow from a region of the heart, a condition termed ischaemia. Current therapy is to reopen the artery but blood flow is seldom restored before a significant amount of the heart muscle has died. Because lost heart muscle cannot be regenerated the patient is left with a weakened heart and heart failure often occurs.

Our research is directed toward identifying therapies that prevent cell death in ischaemic heart. We have found that both population of G-coupled adenosine receptors and activation of the nitric oxide-PKG pathway just before the restoration of blood flow (reperfusion) makes the heart very resistant to cell death.

Our current research is directed at understanding the complex signal transduction pathways involved. We study these pathways using a model mirroring the pathophysiological events during an acute heart attack where we measure tissue death after a standardised ischemic insult as an end-point. We can then use pharmacological tools to both trigger and block the protection at specific points in the given pathway.

Secondly, we study isolated heart muscle cells as well as isolated mitochondria where protection can be analysed with certain techniques and the chemical signals can be measured directly using protein chemistry.

Keywords

myocardial ischaemia ; mitochondria ; reperfusion injury

Key Publications

More recent publications are available through PubMed:

Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu C-H, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T*, Murphy MP*. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014;515:431-5. doi:10.1038/nature13909.  * joint corresponding author.

Kohlhauer M, Dawkins S, Costa ASH, Lee R, Young T, Pell VR, Choudhury RP, Banning AP, Kharbanda RK, Saeb-Parsy K, Murphy MP, Frezza C, Krieg T*, Channon KM*. Metabolomic profiling in acute ST-segment-elevation myocardial infarction identifies succinate as an early marker of human ischemia-reperfusion injury. J Am Heart Assoc 2018;7(8): e007546. doi: 10.1161/JAHA.117.007546.  * joint corresponding author.

Antonucci S, Mulvey JF, Burger N, Di Sante M, Hall AR, Hinchy EC, Caldwell ST, Gruszczyk AV, Deshwal S, Hartley RC, Kaludercic N, Murphy MP, Di Lisa F, Krieg T. Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis. Free Radic Biol Med. 2019;134:678-687. doi: 10.1016/j.freeradbiomed.2019.01.034.

Pell VR, Spiroski A-M, Mulvey J, Burger N, Costa ASH, Logan A, Gruszczyk AV, Rosa T, James AM, Frezza C, Murphy MP, Krieg T. Ischemic preconditioning protects against cardiac ischemia reperfusion injury without affecting succinate accumulation or oxidation. J Mol Cell Cardiol. 2018;123:88-91. doi: 10.1016/j.yjmcc.2018.08.010.

Chouchani ET, James AM, Methner C, Pell VR, Prime TA, Erickson BK, Forkink M, Lau GY, Bright TP, Menger KE, Fearnley IM, Krieg T, Murphy MP. Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia. J Biol Chem. 2017;292:14486-95. doi: 10.1074/jbc.M117.798744.

Kohlhauer M, Pell VR, Burger N, Spiroski AM, Gruszczyk A, Mulvey JF, Mottahedin A, Costa ASH, Frezza C, Ghaleh B, Murphy MP, Tissier R, Krieg T. Protection against cardiac ischemia- reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive. Basic Res Cardiol 2019;114:18, doi:10.1007/s00395-019-0727-0.

Pell VR, Chouchani ET, Frezza C, Murphy MP, Krieg T. Succinate metabolism: a new therapeutic target for myocardial reperfusion injury. Cardiovasc Res. 2016;111:134-41.  doi:10.1093/cvr/cvw100.

Logan A, Pell VR, Shaffer KJ, Evans C, Stanley NJ, Robb EL, Prime TA, Chouchani ET, Cochemé HM, Fearnley IM, Vidoni S, James AM, Porteous CM, Partridge L, Krieg T, Smith RA, Murphy MP. Assessing the mitochondrial membrane potential in cells and in vivo using targeted click chemistry and mass spectrometry. Cell Metab. 2016;23:379-85. doi:10.1016/j.cmet.2015.11.014

Pell VR, Chouchani ET, Murphy MP, Brookes PS, Krieg T. Moving forwards by blocking back-flow: the yin and yang of MI therapy. Circ Res 2016;118:898-906.  doi:10.1161/CIRCRESAHA.115.306569. 

Chouchani ET, Pell VR, James AM, Work LM, Saeb-Parsy K, Frezza C, Krieg T, Murphy MP. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab 2016;23:254-63. doi: 10.1016/j.cmet.2015.12.009.

Methner C, Chouchani ET, Buonincontri G, Sawiak SJ, Murphy MP, Krieg T. Mitochondria selective S-nitrosation by MitoSNO protects against post-infarct heart failure in mouse hearts. Eur J Heart Fail 2014;16:712-7. doi:10.1002/ejhf.100.

Chouchani ET, Methner C, Buonincontri G, Hu CH, Logan A, Sawiak SL, Murphy MP, Krieg T. Complex I deficiency due to selective loss of nudfs4 in the mouse heart results in severe hypertrophic cardiomyopathy. PLoS One 2014;9:e94157. doi:10.1371/journal.pone.009157.eCollection2014.

Methner C, Buonincontri G, Hu CH, Vujic A, Kretschmer A, Sawiak S, Carpenter A, Stasch JP, Krieg T. Riociguat reduces infarct size and post-infarct heart failure in mouse hearts: Insights from MRI/PET imaging. PLoS One 2013;8:e83910. doi:10.1371/journal.pone.0083910.

Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cochemé HM, Reinhold J, Lilley KS, Partridge L, Fearnley IM, Robinson AJ, Hartley RC, Smith RAJ, Krieg T, Brookes PS, Murphy MP. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 2013;19:753-9. doi:10.1038/nm.3212.

Methner C, Lukowski R, Grube K, Loga F, Smith RAJ, Murphy MP, Hofmann F, Krieg T. Protection through postconditioning or a mitochondria-targeted S- nitrosothiol is unaffected by cardiomyocyte- selective ablation of protein kinase G. Basic Res Cardiol 2013,108:337. doi:10.1007/s00395-013-0337-1.

Buonincontri G, Methner C, Carpenter TA, Hawkes RC, Sawiak SJ, Krieg T. MRI and PET in Mouse Models of Myocardial Infarction. J Vis Exp. 2013;(82). doi:10.3791/50806.

Schmidt K, Tissier R, Ghaleh B, Drogies T, Felix SB, Krieg T. Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion. Eur Heart J 2010;31:1655-1662. doi:10.1093/eurheartj/ehp555.

Krieg T, Liu Y, Rütz T, Methner C, Yang X-M, Dost T, Felix SB, Stasch J-P, Cohen MV, Downey JM. BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post- conditions rabbit and rat hearts. Eur Heart J 2009;30:1607-1613. doi:10.1093/eurheartj/ehp143.

Maas O, Donat U, Frenzel M, Rütz T, Kroemer HK, Felix SB, Krieg T. Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG. Br J Pharmacol 2008;154:25-31. doi:10.1038/bjp.2008.71.

Krieg T, Cui L, Qin Q, Cohen MV, Downey JM. Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF. J Mol Cell Cardiol 2004;36:435-443. doi:10.1016/j.yjmcc.2003.12.013.

 

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