Research Interest
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. We plan to apply our findings to target potentially protective proteins to mitochondria by overexpression, thereby increasing the cardiomyocytes' resistance against oxidative stress.
Another component important in protection of the heart from stress are ion channels. A case in point are ATP-sensitive potassium channels (KATP) that are expressed in the sarcolemmal membrane and couple the metabolic state of the cell with the membrane excitability. They serve as an important component in the cardioprotective phenomenon of ischemic or pharmacological preconditioning. We are dissecting the molecular mechanisms by which volatile anesthetics modulate this channel. To investigate the mechanism of anesthetic-channel interaction, we are evaluating the effects of pH and isoflurane on the sarcKATP channel subunits, the channel pore inward rectifier Kir6.2 and the regulatory sulfonylurea receptor SUR2A in a heterologous expression system, applying site-directed mutagenesis.
In other ongoing or just starting projects, we study the impact of near infrared light (670 nm) on the heart and mitochondria after ischemia. Exposure of the ischemic heart with this light at the time of reperfusion turns out to be protective, and mitochondria may play a crucial role in the mechanism behind this phenomenon. Projects are performed in collaboration with investigators from the Anesthesiology, the Pharmocology and Toxicology and the Physiology department.
Recent Publications
Jamnicki-Abegg M, Weihrauch D, Pagel PS, Kersten JR, Bosnjak ZJ, Warltier DC, Bienengraeber MW: Isoflurane inhibits cardiac myocyte apoptosis during oxidative and inflammatory stress by activating Akt and enhancing Bcl-2 expression. Anesthesiology 103:1006-1014, 2005.
Stadnicka A, Marinovic J, Bienengraeber M, Bosnjak ZJ. Impact of In Vivo Preconditioning by Isoflurane on Adenosine Triphosphate-sensitive Potassium Channels in the Rat Heart: Lasting Modulation of Nucleotide Sensitivity during Early Memory Period. Anesthesiology 104:503-510, 2006.
Bienengraeber M, Warltier DC, Bosnjak ZJ, Stadnicka A. Mechanism of cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel activation by isoflurane in a heterologous expression system. Anesthesiology 104: 534-540, 2006.
Ljubkovic M, Marinovic J, Fuchs A, Bosnjak ZJ, Bienengraeber M. Targeted epression of Kir6.2 in mtochondria cnfers potection against hpoxic sress. J Physiol 577: 17-29, 2007.
Ljubkovic M, Mio Y, Marinovic J, Stadnicka A, Warltier DC, Bosnjak ZJ, Bienengraeber M. Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation. Am J Physiol Cell Physiol 292: C1583-C1590, 2007.
Ozcan C, Terzic A, Bienengraeber M. Effective pharmacotherapy against oxidative injury: alternative utility of an ATP-sensitive potassium channel opener. J Cardiovasc Pharmacol 50:411-418, 2007.
Marinovic J, Ljubkovic M, Stadnicka A, Bosnjak ZJ, Bienengraeber M. Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection. Am J Physiol Heart Circ Physiol 294; H1317-H1325, 2008.
Karger AB, Park S, Reyes S, Bienengraeber M, Dyer RB, Terzic A, Alekseev AE. Role for SUR2A ED domain in allosteric coupling within the KATP channel complex. J Gen Physiol 131; 185-96, 2008.