© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Mitochondria as common endpoints in early and late preconditioning
Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, 35392 Gießen, Germany
* Tel.: +49-641-9947-246; fax: +49-641-9947-219. gerhild.taimor{at}physiologie.med.uni-giessen.de
See article by Rajesh et al. [5] (pages 297–307) in this issue.
Preconditioning is a phenomenon in which short periods of non-lethal ischemia protect the heart against subsequent prolonged ischemic periods. This protective effect, caused by ischemic preconditioning (IPC), has two windows: The early window protects the heart against damage caused by an immediately subsequent, prolonged ischemia and lasts up to 2 to 3 hours, whereas the second window of IPC protects against prolonged ischemia, reappearing 24 hours after the preceding IPC and lasting 3 to 4 days. This extended duration of late preconditioning makes it an ideal target for therapeutic use, and its underlying mechanisms have therefore been the subject of extensive research during recent years.
It became obvious that late preconditioning can be induced by a wide variety of stimuli, i.e. ischemia, heat stress, oxygen radicals, nitric oxide, adenosine or opioid receptor agonists. A number of these stimuli are also involved in early preconditioning. Evidence for different mechanisms leading to early and late IPC came from studies of Rizvi et al. [1], showing that only late IPC is dependent on the synthesis of new proteins. This requirement of new proteins is reflected in the time needed for this protection to appear.
Although this fundamental difference between early and late IPC has been documented, it seems as if the signaling pathways meet at the same point: the mitochondria. Mitochondrial KATP channels have been shown to be involved in early IPC [2]. Opening of these channels reduces Ca2+ overload of mitochondria and may therefore prevent metabolic failure of cardiomyocytes. Opening of these channels also decreases necrotic and apoptotic cell death in late IPC [3]. A second endpoint of protection on the mitochondrial level has also been described: IPC can inhibit opening of the mitochondrial transition pore (PTP) in ischemic reperfused myocardium. This was first described for early preconditioning [4] and is now also found for late preconditioning in the study of Rajesh et al., published in this issue [5]. Inhibition of PTP opening may confer cellular protection because PTPs are known to induce cell death upon opening, either by increasing matrix volume resulting in rupture of mitochondria or by cytochrome c release, which is a trigger of apoptotic cell death.
As now demonstrated by Rajesh et al. [5], this protection against PTP opening in late IPC goes along with an increased expression of Bcl-2. The Bcl-2 family is commonly known to comprise anti- and pro-apoptotic proteins. However, family members have also been shown to be involved in necrotic cell death. The family members Bax and Bak interact with PTP directly, thereby facilitating pore opening. This interaction of Bax/Bak with mitochondria can be inhibited by Bcl-2. Therefore, elevation of Bcl-2 expression in late IPC suggests functional involvement of Bcl-2 in depression of PTP opening. Increased Bcl-2 expression on the mRNA level has also been demonstrated in protocols of early preconditioning [6]. Although this expression was not correlated with inhibition of PTP opening, the Bcl-2 increase in early preconditioning suggests similar mechanisms for PTP inhibition as found under late preconditioning.
Besides the control of PTPs by Bcl-2, one should keep in mind that opening of KATP channels in early and late IPC may also be needed for PTP closure. This is because PTP opening can be induced by high mitochondrial Ca2+ levels or ATP depletion. Such conditions are found in ischemic-reperfused myocardium. Opening of KATP channels due to IPC decreases these factors by reduction of Ca2+ overload in mitochondria and by improvement of mitochondrial energy production during reperfusion. Therefore, this might be an additional control of PTP closure in early and late IPC.
In conclusion, common endpoints in the mechanisms of early and late preconditioning have been identified on the mitochondrial level, including the opening of KATP channels, increased Bcl-2 expression, and the inhibition of PTP opening. The question remains, however, as to why these common endpoints are reached at such diverse time points.
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- Rizvi A., Tang X.L., Qiu Y., Xuan Y.T., Takano H., Jadoon A.K., Bolli R. Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning. Am J Physiol. (1999) 277(3 Pt 2):H874–H884.[Web of Science][Medline]
- Gross G.J., Auchampach J.A. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res. (1992) 70(2):223–233.
[Abstract/Free Full Text] - Takashi E., Wang Y., Ashraf M. Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res. (1999) 85(12):1146–1153.
[Abstract/Free Full Text] - Hausenloy D.J., Maddock H.L., Baxter G.F., Yellon D.M. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res (2002) 55(3):534–543.
[Abstract/Free Full Text] - Rajesh K.G., Sasaguri S., Zhitian Z., Suzuki R., Asakai R., Maeda H. Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression. Cardiovasc Res (2003) 59:297–307.
[Abstract/Free Full Text] - Maulik N., Engelman R.M., Rousou J.A., Flack J.E. 3rd, Deaton D. Das D.K. Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation. (1999) 100(19 Suppl):II369, II375.
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