FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.2.1

Title of the proposal

Increase of ischemic tolerance of the myocar-dium. The role of nitric oxide synthases.

Institute

Slovak Academy of Sciences, Institute for Heart Research
Dubravska cesta 9, 842 33 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

Comparative study of nitric oxide synthases ( NOS 1,2,3) immunoreactivity in neonatal and adult rat cardiomyocytes in vitro and in vivo as well as in the myocardium of human patients with dilative cardiomyopathy were used to clarify the immunoreactivity of NOSs in cardiomyocytes in our laboratory last several years. Our study was the first description of the subcellular localization of NOSs in cardiomyocytes. We found that NOS2 isozyme is constitutively expressed in cardiomyocytes both in vitro and in vivo. Physiological and pathophysiological roles of NOS2 may be determined by their association with mitochondria and along contractile fibers. Endogenously derived NO may regulate cardiac muscle function. The effect may be modified and dependent on reactive oxygen intermediates.
Mitochondrially located NOS2 may be regarded as a ubiquitous regulator of mitochondrial oxidative phosphorylation in mammalian cells. Under conditions of ischemia and reperfusion active oxygen species and their intermediates in conjunction with increased NO production can upregulate the expression of protective proteins determining the second window of protection. Therefore we hypothesise that increased expression of nitric oxide synthases could be an intermediate step in the pathway leading to the enhanced late ischemic tolerance of the heart to ischemia. Hence, NO is implicated as a trigger in this model of preconditioning via activation of inducible NOS isoform. Presented and future work sets the stage for additional studies in the area of preconditioning, especially with respect to detailed identification of the signaling cascade triggered by precondioning procedures. Identification of cytoplasmic events associated with NO-signalling pathways may contribute to the development of new cardioprotective agents.

Recent international cooperation of the research team

- Max Planck Institut fur Physiol. Klin., Forschung, Bad-Nauheim, Germany ;
- Inst. of Cardiovasc. Sci., University of Manitoba, Faculty of Manitoba, Winnipeg, Canada;
- Department of Pharmacology, School of Medicine, University of Debrecen, Hungary;
- Department of Pharmacology, Faculty of Medicine, University of Szeged, Hungary;
- The Hebrew University – Hadassah Medical School Jerusalem, Israel;
- Interdisziplinares Zentrum fur Klinische Forschung (IZKF), Munster, Germany;

Proposer´s relevant publications related to the research subject

- Slezak J. at all: Cellular distribution and role of H2O2 during ischemia and early reperfusion. In: The Adapted Heart. Eds.: M.Nagano, N. Takeda, N.S. Dhalla, Raven Press, Ltd., New York, 221-230, 1994
- Slezak J. at all: Hydrogen peroxide changes in ischemic and reperfused heart. Cytochemical and x-ray microanalysis. Amer. J. Pathology 147, 1995: 772-781
- Buchwalow I.B., Schulze W., Karczewski P., Kostic M.M.m, Wallukat G., Morwinski R., Krause E.G., Muller J., Paul M., Slezak J., Luft F.C., Haller H.: Inducible nitric oxide synthase in the myocard, Molecular and Cellular Biochemistry 2001, vol. 217, No. (1-2), p. 73-82.
- Ravingerova T., Barancik M., Pancza D., Styk J., Ziegelhoffer A., Schaper W., Slezak J.: Contribution to the factors involved in the protective effect to ischemic preconditioning: the role of catecholamines and protein kinase C, Annals of the New York Academy of Sciences, 793, 1996: 43-54
- Buchwalow I.B., Schulze W., Slezak J., Luft F.C., Haller H.: Biochemical and physical factors involved in reducing nitric oxide bioactivity in hypertensive heart and kidney. Circulation, 98: 604