Mitochondria constitute the core of cellular energy metabolism as the site of the greatest ATP production. In addition, they play an important role in regulating ionic homeostasis of the cell. It has been suggested that mitochondrial dysfunction may be the major cause for tissue injury during cardiac ischemia and reperfusion. On the other hand, they present a valuable target for triggering protective mechanisms. Exposure of the heart to volatile anesthetics like isoflurane before or after an ischemic event helps to maintain cellular and mitochondrial function in the whole heart, in cardiomyocytes and in isolated mitochondria. One of my research interests revolves around the role of mitochondria as triggers and effectors in protection of the heart from ischemia and stress. We use physiological, pharmacological and molecular techniques as well as proteomics to demonstrate quantifiable alterations in mitochondrial bioenergetics and protein expression during or after exposure to volatile anesthetics.
In a project which in May 2010 received NIH R01 funding, we study the impact of far red/near infrared light (670 nm) on the heart and mitochondria during cardiac ischemia and reperfusion injury. Exposure of the ischemic heart with a LED light source at the time of reperfusion turns out to reduce injury. Mitochondria may play a crucial role in the mechanism behind this phenomenon. In addition, nitric oxide from unconventional sources such as myoglobin or hemoglobin is involved. Projects are performed in collaboration with investigators from the Anesthesiology, the Pharmacology and Toxicology, the Physiology and the Biophysics department.
While the cardioprotective strategies we are studying are extremely powerful in healthy, young animals, diseases such as diabetes diminish their efficacy and limit clinical applicability. Therefore, in collaboration the MCW Human and Molecular Genetics center we examine a rat model of diabetes with mutations in the mitochondrial DNA, which produces a diabetic phenotype as a background for evaluating cardioprotective mechanisms. Interestingly, near infrared light still protects against cardiac ischemia and reperfusion injury during diabetes.
Mio Y, Shim YH, Richards E, Bosnjak ZJ, Paul S. Pagel PS, Bosnjak ZJ, Bienengraeber M. Xenon Preconditioning: Role of Prosurvival Signaling, Mitochondrial Permeability Transition, and Bioenergetics in Rats. Anesth Analg 108: 858-66, 2009.
Zhang R, Mio Y, Pratt PF, Lohr N, Warltier DC, Whelan HT, Zhu D, Jacobs ER, Medhora M, Bienengraeber M. Near infrared light protects cardiomyocytes from hypoxia and reoxygenation injury by a nitric oxide dependent mechanism. J Mol Cell Cardiol 46: 4-14, 2009.
Lohr NL, Keszler A, Pratt P, Bienengraeber M, Warltier DC, Hogg N. Enhancement of nitric oxide release from nitrosyl hemoglobin and nitrosyl myoglobin by red/near infrared radiation: Potential role in cardioprotection. J Mol Cell Cardiol 47: 256-63, 2009.
Pravdic D, Mio Y, Sedlic F, Pratt PF, Warltier DC, Bosnjak ZJ, Bienengraeber M. Isoflurane protects cardiomyocytes and mitochondria by immediate and cytosol-independent action at reperfusion. Br J Pharmacol 160 :220-32, 2010.
Hirata N, Shim YH, Pravdic D, Lohr NL, Pratt PF, Weihrauch D, Kersten JR, Warltier DC, Bosnjak ZJ, Bienengraeber M. Isoflurane differentially modulated reactive oxygen species production via forward versus reverse electron transport flow: Implications for preconditioning. Anesthesiology 115:531-40, 2011.