The involvement of superoxide and iNOS-derived NO in cardiac dysfunction induced by pro-inflammatory cytokines

Cardiovascular Research Group, Department of Pharmacology and Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 4-62 HMRC, Edmonton, AB, Canada T6G 2S2.
Journal of Molecular and Cellular Cardiology (Impact Factor: 4.66). 11/2005; 39(5):833-40. DOI: 10.1016/j.yjmcc.2005.07.010
Source: PubMed


Pro-inflammatory cytokines have been shown to depress myocardial mechanical function by enhancing peroxynitrite generation in the heart. The contribution of NO synthesized by different NOS isoforms, as well as the contribution of superoxide to this mechanism are still not clear. Isolated working hearts of iNOS(-/-) and wildtype mice were perfused for 120 min in the presence or absence of a mixture of pro-inflammatory cytokines (IL-1beta, TNF-alpha, and IFN-gamma). iNOS mRNA was detected only in cytokine-treated wildtype hearts. In wildtype hearts, cytokine treatment significantly decreased cardiac work, calculated as cardiac output times peak systolic pressure, to 31+/-9% of original values by the end of perfusion (P <0.05). The decline of cardiac work induced by cytokine treatment was significantly reduced in iNOS(-/-) hearts (63+/-5% of original value). Only cytokine-treated wildtype hearts showed decreased aconitase activity, indicating a higher level of oxidative stress in these hearts. Cytokines increased NADPH oxidase activity in both wildtype and iNOS(-/-) hearts, whereas NADH oxidase and xanthine oxidase/xanthine dehydrogenase activities were unaffected. The SOD mimetic MnTE2PyP prevented the cytokine-induced decline of cardiac work in both wildtype and iNOS(-/-) hearts. Cardiac p38 MAPK activation was unaltered in all experimental groups. Although genetic disruption of the iNOS gene provides partial protection against cytokine-induced cardiac dysfunction, iNOS-independent mechanisms, including contribution of NO from other NOS enzymes and the generation of superoxide, are also important contributors.

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    • "A number of studies provided evidence for both NOindependent [3–7] and NO-dependent [8–13] mechanisms of contractile depression following cytokines exposure in vitro and in vivo; NO was similarly involved in the depressed myocardial responsiveness to catecholamines observed in patients with heart failure, a condition also associated with systemic inflammation [14] [15] [16] [17]. Although much of the evidence points to the inducible isoform of nitric oxide synthase (or iNOS) as the source of myocardial or systemic NO [9] [10] [11] [12] [13] it may not be the only isoform involved. Indeed, early studies suggested that cytokines may acutely depress cardiomyocyte contraction through activation of a constitutively expressed NOS [18] [19], although the identity of the isoform was not resolved. "
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    ABSTRACT: To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression. beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice. beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.
    European Journal of Heart Failure 12/2007; 9(12):1163-71. DOI:10.1016/j.ejheart.2007.10.006 · 6.53 Impact Factor
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    ABSTRACT: Among the mechanisms of arterial pressure control, the humoral one carried out by the nitric oxide (NO) has aroused great scientific interest. The cardiovascular effects observed after the physical training are associated to an increase in the vascular structure, resting bradycardia and a post effort hypotension effect. The NO that is synthesized in endothelial cells from the L-arginine amino acid with the nitric oxide synthase (NOS) action is considered a powerful vaso-dilator. The NO has three enzymatic isoforms: the nNOS enzyme is present in the nervous cells, and the eNOS in the endothelial cells, both calcium- dependent. On the other hand, the iNOS which is activated by immunological stimuli, is calcium- independent. In the central nervous system (CNS), the NO exerts an important role in the blood pressure control through sympathetic nervous system, inhibiting its activity and decreasing the vascular tonus. Moreover, the NO exerts an influence on the rostral ventrolateral medulla (R VLM), which is important in the modulation of the cardiovascular function. Studies that relate physical training and NO, noticed a significant increase in vasodilation after physical training in special population such as: hypertensives, obese, diabetic and cardiopath people, when compared with healthy individuals. In this sense, there seems to be a modulation of the physical training on the NO participation in the P A control, not only in the peripherical but also in the
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