Nitroxyl enhances myocyte Ca2 transients by exclusively targeting SR Ca2 -cycling

Kohr, Mark J.; Kaludercic, Nina; Tocchetti, Carlo G.; W, Dong Gao; Kass, Da.; Pm, Janssen; Paolocci, Nazareno; Mt, Ziolo

doi:10.2741/e118

Cited by 30 publications

(15 citation statements)

References 42 publications

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“…This cellular behavior was also very different from that induced by the NO donor, DEA/NO. Importantly, HNO does not alter L-type calcium channel current 16 nor augment SR calcium load 19 , in contrast to agents that generate inotropy by elevating cAMP. Subsequent work revealed a direct impact on enhancing myofilament calcium sensitivity 15 .…”

Section: Discussionmentioning

confidence: 93%

“…In myocytes, HNO enhances sarcoplasmic reticular calcium uptake and release via cysteine modifications on SERCA2a 19, 20 , phospholamban 21, 22 and the ryanodine receptor 19 , and also improves myofilament calcium sensitivity 15, 23 . HNO does not alter L-type calcium channel current nor total SR calcium load 16 . Unlike its myocyte effects, vasodilation from HNO has been attributed to soluble guanylate cyclase activation 24, 25 though other pathways remain possible.…”

mentioning

confidence: 84%

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Nitroxyl (HNO)

Sabbah

Tocchetti

Wang

et al. 2013

Circ: Heart Failure

109

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Background The nitroxyl (HNO) donor, Angeli’s salt (AS), exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cyclic AMP-independent. Its clinical utility is limited by chemical instability and co-generation of nitrite that itself has vascular effects. Here we report on effects of a novel, stable, pure HNO donor (CXl-1020) in isolated myoctyes, and intact hearts in experimental models and in patients with heart failure (HF). Methods and Results CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular-myocytes, it dose-dependently increased sarcomere shortening by 75–210% (50–500 µM), with a ~30% rise in the peak Ca2+ transient only at higher doses. Neither protein-kinase-A or soluble guanylate-cyclase inhibition altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced LV end-diastolic pressure and myocardial oxygen-consumption while increasing ejection fraction from 27 to 40% and maximal ventricular power index by 42% (both p<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance, and provided veno-arterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly. Conclusions These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function, and show first-in-man evidence for potential utility in heart failure. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 84%

Nitroxyl (HNO)

Sabbah

Tocchetti

Wang

et al. 2013

Circ: Heart Failure

109

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“…Increased resting force was observed for intact muscle, but not skinned preparations, and only high HNO concentrations which correlated with an increase in diastolic calcium, consistent with previous findings. 13,14 Alterations of TM positional equilibrium by PTMs have been demonstrated by several recent studies using C-terminus truncated troponin I. 34–36 …”

Section: Discussionmentioning

confidence: 96%

“…HNO is capable of forming disulfide bonds and has been shown to enhance in vivo cardiac inotropy; 46,47 while the levels of ROS 14 or NO necessary to induce disulfide bonds have been associated with wider cellular dysfunction and, in the case of myocardium, diminished contractility. 48 It is likely the distinct chemistries of these oxidative species are the source of the difference.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Conversely, cardiac muscles superfused with donors of the thiophylic RNS agent, nitroxyl (HNO), increased force production. 13 This increase in function is notably larger than can be accounted for by the associated rise in Ca 2+ transient, 13,14 suggesting HNO acts directly on the myofilaments, sensitizing them to Ca 2+ . 15 HNO reacts with the thiol on Cys forming either a sulfinamide or, in the presence of an additional free thiol, a disulfide bond (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Nitroxyl-Mediated Disulfide Bond Formation Between Cardiac Myofilament Cysteines Enhances Contractile Function

Gao

Murray

Tian

et al. 2012

Circulation Research

104

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Rationale In the myocardium, redox/cysteine modification of proteins regulating Ca2+ cycling can affect contraction and may have therapeutic value. Nitroxyl (HNO), the one electron reduced form of nitric oxide, enhances cardiac function in a manner that suggests reversible cysteine modifications of the contractile machinery. Objective To determine the effects of HNO modification in cardiac myofilament proteins. Methods and Results The HNO-donor, 1-nitrosocyclohexyl acetate (NCA), was found to act directly on the myofilament proteins increasing maximum force (Fmax) and reducing the concentration of Ca2+ for 50% activation (Ca50) in intact and skinned cardiac muscles. The effects of NCA are reversible by reducing agents and distinct from those of another HNO-donor Angeli’s salt (AS), which was previously reported to increase Fmax without affecting Ca50. Using a new mass spectrometry capture technique based on the biotin switch assay, we identified and characterized the formation by HNO of a disulfide linked actin-tropomyosin and myosin heavy chain (MHC)-myosin light chain 1 (MLC1). Comparison of the NCA and AS effects with the modifications induced by each donor indicated the actin-tropomyosin and MHC-MLC1 interactions independently correlated with increased Ca2+ sensitivity and force generation, respectively. Conclusions HNO exerts a direct effect on cardiac myofilament proteins increasing myofilament Ca2+ responsiveness by promoting disulfide bond formation between critical cysteine residues. These findings indicate a novel, redox-based modulation of the contractile apparatus which positively impacts myocardial function, providing further mechanistic insight for HNO as a therapeutic agent.

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