Overexpression of Endothelial Nitric Oxide Synthase Attenuates Cardiac Hypertrophy Induced by Chronic Isoproterenol Infusion.

Ozaki, Masanori; Kawashima, Seinosuke; Yamashita, Tomoya; Hirase, Tetsuaki; Ohashi, Yoshitaka; Inoue, N.; Hirata, Ken–ichi; Yokoyama, Mitsuhiro

doi:10.1253/circj.66.851

Cited by 78 publications

(68 citation statements)

References 28 publications

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“…We previously reported that overexpression of eNOS attenuated cardiac hypertrophy induced by chronic isoproterenol infusion. 31 Other studies have proven that LV performance was improved and compensatory hypertrophy was reduced after MI in eNOS-overexpressing mice. 14,15 In addition, eNOS deficiency was associated with maladaptive remodeling after MI having increased cardiac hypertrophy and reduced LV function.…”

Section: Discussionmentioning

confidence: 98%

Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

Masano

Kawashima

Toh

et al. 2008

Circ J

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eleterious left ventricular (LV) remodeling after myocardial infarction (MI) is the major cause of heart failure. Although therapeutic strategies designed to limit ventricular remodeling after MI can decrease the incidence of congestive heart failure and improve survival, 1 mechanisms of remodeling process remain not fully elucidated. At the cellular level, reactive oxygen species (ROS) and oxidative stress play a key role in regulating myocardial remodeling. 2,3 In the stressed heart, there is an increase in the production of superoxide from multiple sources such as mitochondria, 4 NADPH oxidase, 5 xanthine oxidase, 6 and nitric oxide (NO) synthase. 7,8 NO is a diffusible highly reactive gas formed by 3 NO synthase (NOS) isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The eNOS-derived NO serves to promote vascular homeostasis and might affect cardiac myocyte function. 9 However, NOS itself can generate superoxide under certain pathological conditions. 10 We have reported that transgenic overexpression of eNOS in apolipoprotein E knockout mice paradoxically increased vascular superoxide production because of enzymatic uncoupling of eNOS. 11 These findings could be explained by relative deficiency of the reducing cofactor of eNOS, tetrahydrobiopterin (BH4). BH4 plays a crucial role in facilitating electron transfer from eNOS reductase domain, maintaining the heme prosthetic group in its redox active form, and promoting formation of active NOS homodimer. Therefore, a relative lack of BH4 results in increased superoxide production by promoting eNOS uncoupling. 12,13 NO from eNOS was shown to protect the heart from various stimuli. Previous studies have shown that cardiac remodeling after MI was attenuated in transgenic mice overexpressing eNOS, 14,15 but deteriorated in mice deficient of the eNOS gene (eNOS KO mice). 16 Similarly, pressure overload-induced LV remodeling was exacerbated in eNOS KO mice. 17,18 Takimoto et al investigated the role of eNOS in the LV remodeling induced by transverse aortic constric- Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and ResultsRats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the n...

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Section: Discussionmentioning

confidence: 98%

Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

Masano

Kawashima

Toh

et al. 2008

Circ J

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“…Pathological conditions, such as arterial hypertension, aorta stenosis or coarctation, called pressure overload; or conditions such as aortic failure or interatrial communication, called volume overload, can promote hypertrophy due to the increased cardiomyocyte volume, together with an increase in size and alteration in the quality of the collagen matrix components 5,7 .…”

Section: Pressure And/or Volume Overloadmentioning

confidence: 99%

“…The first evidence that the • NO can present anti-hypertrophic effects in the heart were obtained in spontaneously hypertensive rats (SHR) under chronic treatment with L-arginine 4 . Subsequently, such role of the • NO was confirmed in mice that hyper-expressed endothelial nitric oxide synthase (eNOS), in which the • NO attenuated the heart hypertrophy induced by the chronic infusion of isoprenaline (ISO) 5 , indicating that the endogenous • NO acts as a negative modulator for heart hypertrophy.…”

Section: Introductionmentioning

confidence: 95%

Fatores e mecanismos envolvidos na hipertrofia ventricular esquerda e o papel anti-hipertrófico do óxido nítrico

Garcia¹,

Incerpi²

2008

Arq. Bras. Cardiol.

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SummaryThe left ventricular hypertrophy (LVH) occurs in response to the hemodynamic overload in some physiological and pathological conditions. However, it has not been completely elucidated whether the primary stimulation for the hypertrophy is the mechanical stretching of the heart, neurohumoral factors, or even the interaction of both. These factors are translated inside the cell as biochemical alterations that lead to the activation of second (cytosolic) and third (nuclear) messengers that will act in the cell nucleus, regulating transcription, and will finally determine the genic expression that induces LVH. The LVH is characterized by structural alterations due to the increase in the cardiomyocyte dimensions, the proliferation of the interstitial connective tissue and the rarefaction of the coronary microcirculation. Recently, nitric oxide (• NO) has appeared as an important regulator of cardiac remodeling, specifically recognized as an anti-hypertrophic mediator. Some studies have demonstrated the cellular targets, the anti-hypertrophic signaling pathways and the functional role of• NO. Thus, the LVH seems to develop as a result of the loss of the balance between the pro and the antihypertrophic signaling pathways. This new knowledge about the pro and anti-hypertrophic signaling pathways will allow the development of new strategies in the treatment of pathological LVH.

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“…Their effects are amplified when production of atheroprotective endothelial nitric oxide (NO) is reduced by EC dysfunction. Both increased ROS and reduced endothelial NO [14][15][16][17][18][19] have been implicated in accelerating plaque progression in Apoe -/-mice and are represented in the model.…”

Section: Oxidative Stressmentioning

confidence: 99%

The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/- Mouse

Chan¹,

Vuillaume²,

Bever³

et al. 2012

Biodiscovery

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Overexpression of Endothelial Nitric Oxide Synthase Attenuates Cardiac Hypertrophy Induced by Chronic Isoproterenol Infusion.

Cited by 78 publications

References 28 publications

Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

Fatores e mecanismos envolvidos na hipertrofia ventricular esquerda e o papel anti-hipertrófico do óxido nítrico

The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/- Mouse

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