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CO-induced overexpression of nNOS and iNOS : Implication on heart vulnerability to Ischemia-reperfusion

Introduction: Recently, carbon monoxide (CO) has received a great deal of scientific attention as a biological regulator. Regarding the cardiovascular system, it has been notably reported that endogenous production as well as acute breathing of CO provided cardioprotection [1-5]. However, CO is also a ubiquitous environmental pollutant present in automobile emissions, industrial gases as well as cigarette smoke which impacts on mortality and morbidity from cardiovascular diseases [6]. Recently, we and others reported that chronic exposure to low concentrations of CO, relevant to urban environment, induces pathological changes of cardiomyocyte phenotype, with an associated decrease in antioxidant defences, increase oxidative stress and impairment of Ca 2+ handling [7-11]. We also pointed out that these alterations rendered the heart more vulnerable to ischemia-reperfusion (IR) [12]. In the heart, endothelial NOS (eNOS) neuronal NOS (nNOS) and inducible NOS (iNOS) are well known as key proteins in the modulation of heart sensitivity to IR. eNOS and nNOS are low-output calcium-dependent enzymes, while iNOS is a high-output calciumindependent enzyme. Contrarily to constitutive NOSs, iNOS is expressed in myocardium in response to inflammatory cytokines, such as TNF-α, or oxidative stress [13]. Up-regulation of iNOS expression results in high levels of NO production, which can be detrimental, in a variety of cell types and tissues [14]. Despite it is generally admitted that prolonged CO exposure induces both oxidative [7, 8, 12] and inflammatory stresses in the heart [15], leading to profound rearrangements of the phenotype of myocardial cells, the relationship between chronic exposure to moderate concentrations of CO and the cardiac expression of NOSs has never been challenged. In the present work, we investigated then, whether: i) CO-induced myocardial stress results in changes in the pattern of eNOS/iNOS/nNOS expression, followed by altered levels of NO production; and, ii) altered NO production in CO-exposed rat hearts contributes to pathological effects of CO exposure, subsequently rendering the heart more vulnerable to IR.