Differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts

Kötter, Sebastian; Gout, Laurence; Frieling-Salewsky, Marion von; Müller, Anna Eliane; Helling, Stefan; Marcus, Katrin; Remedios, Cristobal dos; Linke, Wolfgang A.; Krüger, Martina

doi:10.1093/cvr/cvt144

Cited by 110 publications

(142 citation statements)

References 31 publications

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“…Regarding to the magnitude of changes, previously published studies found similar differences as reported here. Increase in PEVK element phosphorylation (Ser-12742 in the rat sequence) was 31% in human HTN (45) and 23% in patients with dilated cardiomyopathy (26), being similar to the 32.6% in mRen2 rats as reported here. A more prominent change (ϳ70% decrease) in PEVK phosphorylation level was found in a different site within the PEVK region of titin (Ser-12884) in a metabolic model of HFpEF (19).…”

Section: Sd Mren2supporting

confidence: 87%

“…We found increased phosphorylation at Ser-12742, without changes in the phosphorylation level of Ser-12884 in mRen2 hearts. PEVK Ser-12742 hyperphosphorylation was previously demonstrated in mice with transverse aortic constriction (22), in an old HTN dog model (18), as well as in human HF (17,26). Moreover, a recent translational work implicated the hyperphosphorylation of the very same site (Ser-12742) in human HFpEF (45).…”

Section: Sd Mren2mentioning

confidence: 85%

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Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

Kov́acs

Fülöp

Kovács

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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A. Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats. Am J Physiol Heart Circ Physiol 310: H1671-H1682, 2016. First published April 8, 2016; doi:10.1152/ajpheart.00842.2015.-Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n ϭ 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats (n ϭ 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 Ϯ 5.32 vs. 127.03 Ϯ 7.56 mmHg in SD, P Ͻ 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 Ϯ 0.09 vs. 2.77 Ϯ 0.08 mg/g in SD, P Ͻ 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca 2ϩ -activated force, and Ca 2ϩ sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 Ϯ 0.04 vs. 1.87 Ϯ 0.08, P Ͻ 0.05), LV isovolumetric relaxation time was longer (43.85 Ϯ 0.89 vs. 28.55 Ϯ 1.33 ms, P Ͻ 0.05), cardiomyocyte passive tension was higher (1.74 Ϯ 0.06 vs. 1.28 Ϯ 0.18 kN/m 2 , P Ͻ 0.05), and lung weight/body weight ratio was increased (6.47 Ϯ 0.24 vs. 5.78 Ϯ 0.19 mg/g, P Ͻ 0.05), as was left atrial weight/body weight ratio (0.21 Ϯ 0.03 vs. 0.14 Ϯ 0.03 mg/g, P Ͻ 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-␣ in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction.Listen to this article's corresponding podcast at http://ajpheart. podbean.com/e/diastolic-dysfunction-in-the-hypertensive-mren2-rat/.renin-angiotensin-aldosterone system; RAAS; hypertension; diastolic dysfunction; passive stiffness; titin phosphorylation NEW & NOTEWORTHYIt is shown that activation of the renin-angiotensin-aldosterone system leads to hypertension and impaired cardiac relaxation associated with increased cardiomyocyte stiffness and hyperphosphorylation of the PEVK region of titin. Moreover, diastolic dysfunction in mRen2 rats occurs without changes in systolic parameters, similarly to human heart failure with preserved ejection fraction.

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Section: Sd Mren2supporting

confidence: 87%

Section: Sd Mren2mentioning

confidence: 85%

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

Kov́acs

Fülöp

Kovács

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…140 This serine was confirmed to be PKA/PKG dependently phosphorylated in a recent mass spectrometric analysis of recombinant N2-Bus. 123 This analysis identified additional phosphosites within N2-Bus, including evolutionary conserved S4010 (PKA-dependent) and S4099 (PKG-dependent), as well as nonconserved S4065 (PKA-dependent) and S4092 (PKG-dependent). ERK2 was also shown in vitro to phosphorylate S4010 within the N2-Bus, along with nonconserved S3918 and S3960.…”

Section: Regulation Of Titin Stiffness By Phosphorylation: Facts and mentioning

confidence: 98%

“…123,[137][138][139][140] Recent work on titin phosphorylation has focused mainly on the disordered spring elements, N2-Bus and PEVK, both of which are substrates of several major PKs activated by well-studied signaling pathways (Figure 6). N2-Bus is phosphorylated in vitro not only by PKA but also by cGMP-dependent PKG, 123,140 ERK2, 141 and the δ-isoform of Ca 2+ /calmodulin-dependent PK-II, Ca 2+ /calmodulin-dependent protein kinase-IIδ (CaMKIIδ). 142,143 The PEVK region is also phosphorylated by CaMKIIδ 142,143 and PKCα.…”

Section: Regulation Of Titin Stiffness By Phosphorylation: Facts and mentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

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286

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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“…For example, Wolfgang Linke and his group work on the giant protein titin which is very sensitive to even very low levels of proteases, so they reasonably assumed that only biopsy samples were likely to be free of degradation. Thus, several years passed before it was discovered (Krüger et al 2009;Hamdani et al 2013;Koetter et al 2013) that the titin in our donors were indeed free of proteolysis. RNAs are also highly sensitive to hydrolysis, but several colleagues have used LV samples from failing and donors with good results including Kuster et al (2013), Kong et al (2010) and Huang et al (2016).…”

Section: Donor Heartsmentioning

confidence: 89%

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease

Remedios

Lal

et al. 2017

Biophys Rev

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The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy This article is part of a Special Issue on 'IUPAB Edinburgh Congress' edited by Damien Hall.Electronic supplementary material The online version of this article

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Differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts

Cited by 110 publications

References 31 publications

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

Gigantic Business

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease

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