Author : Rachel J. Keith
Publisher :
ISBN 13 :
Total Pages : 366 pages
Book Rating : 4.:/5 (649 download)
Book Synopsis Metabolic Pathways of Cardioprotection by : Rachel J. Keith
Download or read book Metabolic Pathways of Cardioprotection written by Rachel J. Keith and published by . This book was released on 2009 with total page 366 pages. Available in PDF, EPUB and Kindle. Book excerpt: Acute myocardial infarction (AMI) is the leading cause of death in the US. Myocardial tissue damage associated with MI is mitigated through cardioprotection afforded by late phase ischemic preconditioning (PC). Known mediators of the late phase ischemic PC, inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1) and aldose reductase (AR), form an effective cardioprotective module that triggers and establishes a preconditioned state. Nevertheless, the specific mechanisms by which preconditioning enhance myocardial resistance to ischemia remain unclear. Our studies demonstrate that overexpression of iNOS is sufficient to confer cardioprotection and that iNOS protects against ischemia-reperfusion injury by decreasing the generation of reactive oxygen species (ROS) and inhibiting mitochondria permeability transition (MPT), without affecting mitochondrial biogenesis or inducing permanent changes in the mitochondrial structure and function. Our studies also show that HO-1 confers increased resistance to MPT and decreases mitochondrial respiration, suggesting that it enhances mitochondrial stability against cellular stress. Cardioprotection due to iNOS and HO-1 seems to relate to an increased state of NO availability, which may be necessary to prevent I/R injury. One of the mechanisms of NO-mediated cardioprotection was found to be related to AR. Increased NO in the heart activates AR, an enzyme involved in the metabolism and detoxification of toxic aldehydes generated during lipid peroxidation. Myocardial I/R injury increases aldehydes, which react with proteins, increasing ER stress. Our studies show that increasing NO or AR in the heart decreases the accumulation of lipid-derived aldehydes and prevents ER stress. Collectively, these data indicate that aldehydes generated from lipid peroxidation associated with I/R trigger the unfolded protein response (UPR) and that increased metabolism of these aldehydes during myocardial I/R via AR prevents ischemia-induced ER stress. These findings support the view that ER stress is a significant component of myocardial I/R injury. Hence, therapeutic strategies for preventing ER stress might be beneficial in preventing tissue injury and dysfunction associated with AMI.