A significant amount of progress has been made in understanding the mechanisms involved (initiating, signaling, and effector components) in the development of delayed PC in the heart. In general, the results of in vivo and in vitro studies tend to be congruent. However, there are some important differences worth noting. In terms of the initiating molecules, ROM generated during the initial stress are critical to the development of delayed PC. However, the source of the ROM after an I/R (or A/R) challenge is not clear, that is, in vivo studies suggest that NO derived from eNOS generates the ROM, while the in vitro studies do not agree with this notion. In terms of the effector molecules, both NOS and Mn-SOD have been implicated as playing important roles. Indeed, there is some indication that these two enzyme systems may act in concert in the development of delayed PC. The only serious controversial issue is whether iNOS or eNOS is the isoform involved, that is, in vivo studies favor a role for iNOS, whereas in vitro studies favor a role for eNOS. In terms of the signaling molecules that link the initiating factors (ROM) and the effector molecules (NOS and SOD), both in vivo and in vitro studies agree that NFkB is pivotal. However, the in vivo studies indicate that NFkB is important in the upregulation of iNOS, whereas the in vitro studies suggest that this transcription factor upregulates Mn-SOD. In vitro studies have also implicated a role for AP-1 as a potentially important nuclear transcription factor in delayed PC. Further complementary in vivo and in vitro studies are warranted to resolve these issues in order for clinical applications of these bench studies to be fully realized.
1. Rui, T., Cepinskas, G., Feng, Q., Ho, Y.-S., and Kvietys, P. R. (2001). Cardiac myocytes exposed to anoxia-reoxygenation promote neutrophil transendothelial migration. Am. J. Physiol. Heart Circ Physiol. 281, H440-H447. This is the first in vitro study to show that there is a communication between cardiac myocytes and endothelial cells during an A/R challenge.
2. Guo, Y., Jones, W. K.. Xuan, Y.-T., Tang, X.-L., Bao, W., Wu, W.-J., Han, H., Laubach, V. E., Ping, P., Yang, Z., Qiu, Y., and Bolli, R. (1999). The late phase of preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc. Natl. Acad. Sci. USA 9 R. 6,
1507-1512. This is the first in vivo study to show that iNOS is the effector component of delayed preconditioning using genetically altered mice.
3. Rui, T., Cepinskas, G., Feng, Q., and Kvietys, P. R. (2003). Delayed preconditioning in cardiac myocytes with respect to development of a proinflammatory phenotype: Role of SOD and NOS. Cardiovasc. Res. 59, 901-911. This is the first in vitro study to demonstrate that eNOS is the effector component of delayed preconditioning using cardiac myocytes and endothelial cells isolated from genetically altered mice. In addition, evidence was provided for an interaction between Mn-SOD and eNOS in the development of delayed preconditioning.
Cepinskas G., Rui, T., and Kvietys, P. R. (2001). Neutrophil-endothelial cell interactions during the development of tolerance to ischemia/reper-fusion in isolated cells. Acta Physiol. Scand. 173, 23-33.
Dawn, B., and Bolli, R. (2002). Role of nitric oxide in myocardial preconditioning. Ann. N. Y. Acad. Sci. 962, 18-41. Hoshida, S., Yamashita, N., Otsu, K., and Hori, M. (2002). The importance of manganese superoxide dismutase in delayed preconditioning: Involvement of reactive oxygen species and cytokines. Cardiovasc. Res. 55, 495-505.
Marber, M. S. (2000). Ischemic preconditioning in isolated cells. Circ. Res. 86, 926-931.
Dr. Tao Rui received his M.D. in 1986 from Nanjing Medical University and his M.Sc. in 1992 from Shanghai Medical University, P.R. China. Currently, he is a postdoctoral researcher at Lawson Health Research Institute, London, Ontario, Canada. His research interests include myocyte oxidative stress, ischemia-reperfusion, and delayed preconditioning.
Dr. Gediminas Cepinskas received his D.V.M. in 1984 from the Lithuanian Academy of Veterinary Sciences. He is a Scientist at Vascular Cell Biology/Inflammation Program at Lawson Health Research Institute, London, Ontario, Canada. His research is focused on the molecular mechanisms of inflammation. In particular, leukocyte-endothelial cell interactions, mechanisms of ischemia-reperfusion tolerance, and cell signaling are the prime subjects of his research.
Dr. Peter R. Kvietys received his Ph.D. in physiology in 1979 from Michigan State University. His research interests include inflammation and ischemia-reperfusion. Dr. Kvietys is a member of the Vascular Cell Biology/Inflammation Program at Lawson Health Research Institute, London, Ontario, Canada, and a Fellow of the Cardiovascular Section of American Physiological Society.
Was this article helpful?
Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!