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The Role of Neuronal Nitric Oxide Synthase (nNOS) in Ischaemia/Reoxygenation-induced injury and in protection of the Mammalian Myocardium

By Anupama Barua

Abstract

Background: In physiological condition, NO is produced by two constitutive NOS isoform; eNOS and nNOS. Both isoforms have specific cellular locations and although the role of eNOS in myocardial ischaemic injury and in cardioprotection has been thoroughly addressed, but the role of nNOS remains unclear. Therefore, the aims of the thesis were to: (i) investigate the role of nNOS in ischaemia/reoxygenation-induced injury, (ii) determine whether its effect is species-dependent, (iii) elucidate the relationship of nNOS with mitoKATP channels and p38MAPK, two key components of IP and (iv) investigate whether modulation of the NO metabolism can overcome the unresponsiveness of the diabetic myocardium to IP. \ud Methods and Results: Ventricular myocardial slices from rats and mice, nNOS knockout mice, and also from human right atrial slices were subjected to 90min ischaemia and 120min reoxygenation (37°C). Muscles were randomized to receive various treatments. Both the provision of exogenous NO and the inhibition of endogenous NO production significantly reduced tissue injury (creatine kinase release, cell necrosis and apoptosis), an effect that was species–independent. The protection seen with nNOS inhibition was as potent as that of IP, however, in nNOS-knocked out mice the cardioprotective effect of non-selective NOS (L-NAME) and selective nNOS inhibition (TRIM) and also that of IP was blocked while the benefit of exogenous NO remained intact. Additional studies revealed that the cardioprotection afforded by of exogenous NO and by inhibition of nNOS were unaffected by the mitoKATP channel blocker 5-HD although it was abrogated by p38MAPK blocker SB203580. Finally, in diabetic myocardium, IP did not decrease CK release neither reduced cell necrosis or apoptosis. In diabetic myocardium NO donor SNAP, inhibitor L-NAME and TRIM significantly reduced CK leakage, cell necrosis and apoptosis. \ud Conclusions: nNOS plays a dual role in ischaemia/reoxygenation on that its presence is necessary to afford cardioprotection by IP but its inhibition reduces myocardial ischaemic injury. The role of nNOS is species-independent and exerted downstream of the mitoKATP channels and upstream of p38MAPK. Moreover, both the provision of exogenous NO and the suppression of endogenous NO production resulted in potent protection of diabetic human myocardium, overcoming the unresponsiveness of these tissues to IP

Publisher: University of Leicester
Year: 2010
OAI identifier: oai:lra.le.ac.uk:2381/8754

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