Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart

Drexler, Helmut; Kästner, Stephanie; Strobel, Armin; Studer, Rebecca K.; Brodde, O.‐E.; Hasenfuß, Gerd

doi:10.1016/s0735-1097(98)00336-2

Cited by 168 publications

(108 citation statements)

References 37 publications

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“…Conversely, high SIN-1 may be mimicking the peroxynitrite production of NOS2, which is considered to be a pathophysiological regulator of cardiac function by reducing β-adrenergic responsiveness [3,36]. During many pathophysiological conditions of the myocardium, nitric oxide production is increased with NOS2 expression [3,42] and superoxide production is increased through NADPH oxidase and/or xanthine oxidoreductase [8,9], leading to supraphysiological peroxynitrite production and cardiac dysfunction. Additionally, this physiological and pathophysiological regulation of cardiac contractility by peroxynitrite likely relies on signaling pathways that target the excitationcontraction coupling protein PLB as well as other targets, thus resulting in the biphasic effect of SIN-1.…”

Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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“…[1][2][3][4] NO has been shown to attenuate cardiac myocyte hypertrophy, [5][6][7][8] to promote cardiac myocyte apoptosis, 9,10 and to modulate cardiac myocyte contractile function. 2,11 Studies in NOS2-deficient and NOS2-overexpressing mice indicate that upregulation of NOS2 is detrimental and may increase mortality in heart failure.…”

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confidence: 99%

Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide

et al. 2003

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Background-In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure. Methods and Results-As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeletonassociated muscle LIM protein (MLP) in endothelin-1 (ET-1)-stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (Ϫ49%, PϽ0.01) and protein (Ϫ52%, PϽ0.01) abundance in ET-1-treated cardiomyocytes via cGMPdependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1␤ and IFN-␥ downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (Ϫ52%, PϽ0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes. Conclusions-NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.

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“…Slično tome, Drexleri sar. [26] sugerišu da L-NMMA ne utiče na kontraktilne performanse srčanih mišićnih ćelija izolovanih iz ljudskog srca u završnom stadijumu srčane insuficijencije. Pozitivne korelacije aktivnosti endokardne i subendokardne i NOS i ecNOS sa ventrikularnim kontraktilnim performansama ukazuju na blagotvorno dejstvo NO oslobođenog iz endotela kod pacijenata sa dilatiranom kardiomiopatijom.…”

Section: Disfunkcija I Aktivacija Vaskularnog Endotelaunclassified

Vascular and endocardial endothelial dysfunction in heart failure

Smiljic¹

2017

Tim Med Glas

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Sažetak:Srčana insuficijencija se definiše kao klinički sindrom koji je posledica poremećaja u strukturi ili funkciji srca što ga onemogućava da zadovolji potrebe organizma za kiseonikom neophodnog za izbalansirani metabolizam svih tkiva. U patogenezi srčane insuficijencije značajno mesto ima aktivacija i disfunkcija endokardnog i vaskularnog endotela. Aktivacija i disfunkcija endotela praćena je funkcionalnim promenama, uključujući promene u autokrinom i parakrinom signaliziranju, u distribuciji i broju receptora, antinflamatornim i antikoagulantnim osobinama. Smatra se da je endotelna disfunkcija nastupila kada izostane očekivana vazodilatacija posredovana azot oksidom endotelnog porekla u odgovoru na acetilholin, bradikinin, supstancu P i/ili serotonin. Nivo endotelina-1 u endokardnom endotelu, u endotelu miokardnih kapilara kao i u kardiomiocitima insuficijentnog srca je povećan. Neuregulin-1 ima ulogu u proliferaciji, diferencijaciji i očuvanju funkcije kardiomiocita. Efekti su posredovani preko seta tirozin kinaza ligand zavisnih receptora ErbB2 ErbB3 i ErbB4. Kod pacijenata sa metastaskim tumorom karcinoma dojke koji su u terapiji primali i monoklonska antitela anti ErbB2, lek trastuzumab, sam ili u kombinaciji sa antraciklinom, češće se javljala srčana insuficijencija i sistolna disfunkcija komora. Koronarna vaskularna endotelna disfunkcija dovodi do koronarne vazokonstrikcije, proliferacije i remodelovanja glatkih mišićnih ćelija, povećanja lipidnih depozita u zidu krvnog suda i moguće koronarne tromboze. Ovi procesi oštećuju koronarne arterije, pogoršavaju miokardnu perfuziju i indirektno doprinose progresivnoj srčanoj insuficijenciji i ishemijskoj miokardiopatiji. Disfunkcija i lezija endokardnog endotela su uvek udruženi sa snažnim promenama u mehaničkim performansama miokarda. Disfunkcija endotela je rani događaj koji vodi ka progresiji srčane insuficijencije. Pri umerenom opterećenju pritiskom kod hipertrofije leve komore potpuno je supresovana ventrikularna relaksacija zbog izostanka oslobađanja endotelnog NO. Zaštita koronarnog endotela od oksidativnog stresa se poboljšava biodostupnošću NO. To značajno popravlja relaksantni odgovor komora na endogeni NO, inhibira razvoj hipertrofije leve komore i srčane insuficijencije. Ključne reči:vaskularni endotel, endokardni endotel, srčana insuficijencija Summary: Heart failure is defined as a clinical syndrome due to disorders in the structure or function of the heart that prevents it from meeting the needs of the organism for the oxygen necessary for the balanced metabolism of all tissues. In the pathogenesis of cardiac insufficiency, the activation and dysfunction of the endocardial and vascular endothelium are significant.Activation and endothelial dysfunction are followed by functional changes, including changes in auto-and paracrine signaling, in the distribution and number of receptors, anti-inflammatory, and anticoagulant features. It is considered that endothelial dysfunction occurred when the expected vasodilatation mediated by nitric oxide of en...

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Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart

Abstract: Cardiac production of NO by NOS II attenuates the positive inotropic effects of beta-adrenergic stimulation and hastens relaxation in failing human hearts.

Cited by 168 publications

References 37 publications

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide

Vascular and endocardial endothelial dysfunction in heart failure

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