Nitric oxide and cardiac function

Rastaldo, Raffaella; Pagliaro, Pasquale; Cappello, Simone; Penna, Cláudia; Mancardi, Daniele; Westerhof, Nicolaas; Losano, G

doi:10.1016/j.lfs.2007.07.019

Cited by 195 publications

(156 citation statements)

References 139 publications

(151 reference statements)

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“…NO participates not only in the control of contractility and heart rate but also limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre-and postconditioning. 16,30,31 Growing evidence suggests that activation of PKG (cGKI) via cGMP signaling can lower diastolic tone and increase LV extensibility. 18 -21 Our work now demonstrates that cGMP-activated PKG phosphorylates specific sites within the titin spring segment and decreases titin-based stiffness by altering the elastic properties of a cardiac-specific titin region, the N2-Bus.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Krüger

Kötter

Grützner

et al. 2009

Circulation Research

358

273

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Abstract-The sarcomeric titin springs influence myocardial distensibility and passive stiffness. Titin isoform composition and protein kinase (PK)A-dependent titin phosphorylation are variables contributing to diastolic heart function. However, diastolic tone, relaxation speed, and left ventricular extensibility are also altered by PKG activation. We used back-phosphorylation assays to determine whether PKG can phosphorylate titin and affect titin-based stiffness in skinned myofibers and isolated myofibrils. PKG in the presence of 8-pCPT-cGMP (cGMP) phosphorylated the 2 main cardiac titin isoforms, N2BA and N2B, in human and canine left ventricles. In human myofibers/myofibrils dephosphorylated before mechanical analysis, passive stiffness dropped 10% to 20% on application of cGMP-PKG. Autoradiography and anti-phosphoserine blotting of recombinant human I-band titin domains established that PKG phosphorylates the N2-B and N2-A domains of titin. Using site-directed mutagenesis, serine residue S469 near the COOH terminus of the cardiac N2-B-unique sequence (N2-Bus) was identified as a PKG and PKA phosphorylation site. To address the mechanism of the PKG effect on titin stiffness, single-molecule atomic force microscopy force-extension experiments were performed on engineered N2-Bus-containing constructs. The presence of cGMP-PKG increased the bending rigidity of the N2-Bus to a degree that explained the overall PKG-mediated decrease in cardiomyofibrillar stiffness. Thus, the mechanically relevant site of PKG-induced titin phosphorylation is most likely in the N2-Bus; phosphorylation of other titin sites could affect protein-protein interactions. The results suggest that reducing titin stiffness by PKG-dependent phosphorylation of the N2-Bus can benefit diastolic function. Failing human hearts revealed a deficit for basal titin phosphorylation compared to donor hearts, which may contribute to diastolic dysfunction in heart failure. Key Words: cGMP Ⅲ nitric oxide Ⅲ diastolic function Ⅲ connectin Ⅲ passive tension M yocardial and chamber diastolic function are influenced by chamber geometry, hypertrophy, the extracellular matrix and the sarcomeric titin springs. Titins are giant proteins which exist in the heart in 2 main isoforms coexpressed in sarcomeres: a shorter, stiffer N2B-titin (3.0 MDa) and longer, more compliant N2BA isoforms (3.2 to 3.7 MDa). Differential expression of these isoforms is related to alternate gene splicing affecting the functionally elastic titin region, which is confined to the sarcomeric I-band. 1 The springy titin segment comprises regions of serially linked immunoglobulin-like (Ig) domains separated by a cardiacspecific N2-B domain and a so-called PEVK segment (rich in proline, glutamate, valine, and lysine residues). The N2BA isoforms additionally have an N2-A domain and contain more Ig domains and PEVK-rich modules compared to the N2B isoform.Differential expression of titin isoforms determines passive stiffness of the sarcomere. 2,3 A low ratio of N2BA:N2B isoforms is found in sarcome...

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Section: Discussionmentioning

confidence: 99%

Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Krüger

Kötter

Grützner

et al. 2009

Circulation Research

358

273

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“…[18][19][20][21] The molecular mechanism(s) of NO under different (patho) physiological conditions, however, has not been completely understood. At the post-translational modification level, the NO related species can cause either tyrosine nitration or cysteine S-nitrosylation of cardiac proteins.…”

Section: Discussionmentioning

confidence: 99%

A Proteomic Study of S-Nitrosylation in the Rat Cardiac Proteins in Vitro

Shi

Feng

et al. 2008

Biological & Pharmaceutical Bulletin

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Protein S-nitrosylation in the heart tissue has been implicated in several patho (physiological) processes. However, specific protein targets for S-nitrosylation remain largely unknown. In this study, the rat cardiac proteins were incubated in vitro with S-nitrosoglutathione (GSNO), a biologically existing nitric oxide (NO) donor and S-nitrosating agent, to induce protein S-nitrosylation, and the resulting S-nitrosylated proteins were purified by the biotin switch method, followed by two-dimensional gel electrophoresis (2-DE) separation and matrix-assisted laser desorption ionization/time of flight tandem mass spectrometry (MALDI-TOF-MS/MS) identification. Candidate Western blot analysis was also used to identify potential S-nitrosylated proteins. A total of ten proteins including triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, creatine kinase, adenylate kinase 1 (AK1), enolase 1, destrin, actin, myosin, albumin and Hsp27 were unambiguously identified, among which AK1 was found as a novel target of S-nitrosylation. Further studies showed that AK1 activity in the rat heart extracts was significantly inhibited by GSNO but not oxidized glutathione (GSSG), and the inhibition was completely reversed by dithiothreitol (DTT) post-treatment, demonstrating that S-nitrosylation might serve as a new regulatory mechanism in controlling AK1 activity. This study represents an initial attempt to characterize the S-nitrosoproteome in the heart and highlights the importance of protein S-nitrosylation in cardio function regulation.

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“…The relationship between endothelial dysfunction and insulin resistance (27) underlies clustering of cardiovascular and metabolic diseases including hypertension, atherosclerosis, diabetes, and obesity (42). Endothelial dysfunction caused by reduced bioavailability of NO plays an important role in the pathogenesis of cardiometabolic syndrome (47,55,57). One of the vascular actions of insulin increases blood flow that facilitates delivery of nutrients and hormones (25,56,65,66).…”

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confidence: 99%