Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease

Ferreiro, Carlos; Chagas, Antônio Carlos Palandri; Carvalho, Maria Helena Catelli de; Dantas, Ana Paula; Scavone, Cristóforo; Souza, Luiz Carlos Bento de; Buffolo, Ênio; Luz, Protásio Lemos da

doi:10.1590/s0100-879x2004000900005

Cited by 36 publications

(25 citation statements)

References 36 publications

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Section: Introductionmentioning

confidence: 99%

“…Increased iNOS activity has been reported in ventricular tissue from patients with dilated cardiomyopathy (6). Increased iNOS activity has also been found in myocarditis, ischemic heart disease, valvular heart disease, and human cardiac allografts, and iNOS levels have been found to correlate with ventricular contractile dysfunction (8,15,20,22). Mungrue et al (19) reported that chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite, which was associated with cardiac hypertrophy and dilatation.…”

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confidence: 99%

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Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

Li¹,

Guo²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction at 3 days after gene transfer. However, the long-term effects of iNOS gene therapy on myocardial ischemic injury and cardiac function are unknown. To address this issue, we used a recombinant adenovirus 5 (Ad5) vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 mo due to lack of inflammation. Mice received intramyocardial injections in the left ventricular (LV) anterior wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 1 or 2 mo later, they were subjected to myocardial infarction (30-min coronary occlusion followed by 4 h of reperfusion). Cardiac iNOS gene expression was confirmed by immunoblotting and activity assays at 1 and 2 mo after gene transfer. In the iNOS group, infarct size (percentage of risk region) was significantly reduced (P < 0.05) both at 1 mo (24.2 ± 3.4%, n = 6, vs. 48.0 ± 3.6%, n = 8, in the LacZ group) and at 2 mo (23.4 ± 3.1%, n = 8, vs. 36.6 ± 2.4%, n = 7). The infarct-sparing effects of iNOS gene therapy were as powerful as those observed 24 h after ischemic preconditioning (23.1 ± 3.4%, n = 10). iNOS gene transfer had no effect on LV function or dimensions up to 8 wk later (echocardiography). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 mo) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy. Keywordsnitric oxide synthase; cardiac function; mouse Although ischemic preconditioning (PC) is known to be a powerful cardioprotective adaptation, it has not yet found clinical application. The late phase of PC would appear particularly suitable for therapeutic exploitation because it is underlain by the upregulation of cardioprotective genes, which, if expressed chronically, could conceivably induce a longlasting PC state (3, 4). Among these genes, the inducible isoform of nitric oxide (NO) synthase (iNOS) has been studied most thoroughly. Extensive evidence over the past decade demonstrates that iNOS is an obligatory mediator of the protection afforded by late PC induced by various stimuli, including ischemia, physical exercise, and various pharmacological agents (1-3, 5). Therefore, upregulation of iNOS appears to be a final common pathway whereby diverse stimuli induce a shift of the heart to a defensive clinically to protect the ischemic myocardium, it is important to determine whether chronic overexpression of iNOS in the myocardium is cardioprotective.In this regard, a number of experimental and clinical results have been interpreted to suggest that enhanced production of NO via iNOS is detrimental to the myocardium (13,20). Increased iNOS activity has been reported in ventricular tissue from patients with dilated cardiomyopathy (6). Increased iNOS activity has also been found in myocarditis, ischemic heart disease, valv...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

Li¹,

Guo²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Taking all these findings together, we consider that the interindividual variation in the level of iNOS expression during the initial phase of repetitive I/R injury may be associated with interindividual variation in the severity of ICM in the advanced stage. iNOS is considered to be associated with the grade of myocardial injury caused by ischemia, 19,20 and in the patient with ICM the level of myocardial iNOS is related to functional recovery after revascularization. 26 iNOS is upregulated by I/R injury 27 through myocardial inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…The second purpose of the present study was to establish an echocardiographic parameter during the initial stage of repetitive I/R injury in the rats that would predict individual severity of ICM in the advanced stage. In addition, inducible nitric oxide synthase (iNOS) expression in the heart, which is known to upregulated by I/R injury 18 and associated with cardiac dysfunction, 19,20 would also be examined in the initial stage of repetitive I/R induced-ICM, to investigate any association with echocardiographic parameters. 90 mg/kg, xylazine: 10 mg/kg), then orally intubated (16G polyethylene tubing) using an otoscope.…”

mentioning

confidence: 99%

Novel Rat Model of Ischemic Cardiomyopathy Induced by Repetitive Myocardial Ischemia/Reperfusion Injury While Conscious

Toyota

Kawaguchi

Ogasawara

et al. 2007

Circ J

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Background A rodent model of ischemic cardiomyopathy (ICM) induced by repetitive brief ischemia/reperfusion (I/R) injury while conscious has not been previously established. Methods and Results A newly developed coronary occluder was implanted in male Wistar rats. A repetitive I/R protocol (20 s, 2 min, followed by main 30 min -ischemia, every 48 h, for 4 weeks) was introduced while the animals were conscious. The I/R protocol did not induce transmural scar formation but induced (1) residual myocytes with scattered infiltration of fibrosis (Masson trichrome stain), (2) coronary hypoperfusion ( 201 Tl-Cl autoradiogram), (3) reduced coronary microvascular volume fraction (microCT), and (4) gradually progressive left ventricular (LV) dilation (echocardiography). These parameters of ICM showed interindividual variation; however, the percent increase in LV diastolic area on day 3 was significantly correlated with LV dilation (r=0.91, p<0.0001), fibrosis (r=0.77, p=0.0034), and reduction in microvessels (r=0.67, p=0.040) at week 4. The LV dilatory response on day 3 also correlated with inducible nitric oxide synthase expression (immunohistochemistry, day 3) in the LV (r=0.92, p=0.028). Conclusions A novel rat model of ICM induced by repetitive I/R while conscious showed interindividual variation in the severity of ICM in the advanced stage, but this was predictable non-invasively (by LV dilatory response) during the initial stage of repetitive I/R. (Circ J 2007; 71: 788 -795)

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“…The endothelial NOS (eNOS) and the neuronal NOS are constitutively expressed and the inducible NOS (iNOS) is biosynthesized in pathological states such as heart failure [127]. At the level of the vasculature, NO is involved in homeostasis, having vasodilator, antiproliferative and antiplatelet actions, as recently reviewed in ref.…”

Section: Nitric Oxide Synthasementioning

confidence: 99%

Enzymatic Targets in Atherosclerosis

Fuior¹,

Trusca²,

Roman³

et al. 2015

J Mol Genet Med

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Atherosclerosis, a prime cause of mortality across the developed societies, was targeted by diverse therapeutic strategies. These evolved in response to the complex etiology and evolution of the disease. Many enzymes are associated with atherosclerosis, either in the main stream of lipid biosynthesis and transport or in the collateral and intertwined pathways of oxidative stress, inflammation, vascular remodeling or chromatin stability and are therefore revised herein. Enzyme exploration led to important developments. At the beginning, there were the statins, derived as inhibitors of hydroxy-methyl-glutaryl CoA (HMG-CoA) reductase, currently used widely to decrease lipid levels. At the other end, the inhibitors of the recently discovered proprotein convertase subtilisin/kexin type 9 (PCSK9) are awaiting the validation in clinical trials with great hopes for the future. In between, one can find some palliatives, as aspirin, an inhibitor of cyclooxygenase (COX), but also many invalidated candidates. Classical pharmacological data and newer approaches, like genetic knockouts in murine atherosclerosis models, are reviewed in order to appreciate the involvement of a particular enzyme in atherogenesis. However, the pursuit of an efficacious drug has been long and, in many cases, disappointing. Conclusions can be drawn from the overview of both successes and failures, in a quest for the best.

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Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease

Cited by 36 publications

References 36 publications

Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

Novel Rat Model of Ischemic Cardiomyopathy Induced by Repetitive Myocardial Ischemia/Reperfusion Injury While Conscious

Enzymatic Targets in Atherosclerosis

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