Titin isoform expression in aortic stenosis

Williams, Lynne; Howell, Neil; Pagano, Domenico; Andréka, Péter; Vértesaljai, Márton; Pecor, Tiffany; Frenneaux, Michael; Granzier, Henk

doi:10.1042/cs20080248

Cited by 36 publications

(26 citation statements)

References 25 publications

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“…This model shows signs of diastolic dysfunction similar to those frequently seen in elderly HFpEF patients: impaired LV relaxation, unaltered coefficient of LV diastolic stiffness and reduced diastolic capacitance, together with elevated natriuretic peptides, normal LV volume but increased LV mass and moderated myocardial fibrosis. However, distinct results have been found in aortic stenosis patients, with either a switch to N2B (Williams et al 2009) or a switch to N2BA (Borbély et al 2009b) compared to a donor (non-failing hearts) group. In another variant of heart disease, hypertrophic cardiomyopathy (Chaturvedi et al 2010), the cardiac titin isoform did not change compared to donor groups.…”

Section: Sarcomeric Proteins: Elastic Filamentsmentioning

confidence: 95%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

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Section: Sarcomeric Proteins: Elastic Filamentsmentioning

confidence: 95%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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“…An increased proportion of the compliant N2BA variants was observed in end-stage failing human hearts, including those from ischemic cardiomyopathy, 105 nonischemic DCM, 109,110 and other patients with HFrEF, 111 compared with nonfailing donor hearts (45%-50% versus ≈30%). In patients with aortic stenosis, the N2BA:N2B expression ratio was somewhat higher than in healthy control hearts in one study, 111 but unaltered 112 or reduced 113 in other studies. In the hearts of mice exposed to transverse aortic constriction, the N2BA:N2B ratio was significantly increased in comparison with healthy mouse hearts.…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

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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“…In both cases, the relative expression of the N2BA/N2B isoforms and their degree of total phosphorylation are similar. However, a relative hypophosphorylation of the more rigid isoform, N2B, was observed in hypertensive cardiomyopathy, which has been proposed as the underlying mechanism to the increase in myocardial rigidity and diastolic dysfunction in this disease 40,45 .…”

Section: Alterations In the Phosphorylation State Of Titinmentioning

confidence: 98%

“…However, the molecular mechanisms underlying the preferential expression of one of the isoforms remains to be elucidated. It is known that in response to different hemodynamic states, long-term alterations in the expression ratio of the two isoforms of titin can occur, which, as we will see next, take place, for instance, in heart failure 15 and aortic stenosis 40,41 .…”

Section: Mechanisms Of Long-term Regulation Of Titinmentioning

confidence: 99%

Papel da titina na modulação da função cardíaca e suas implicações fisiopatológicas

Castro‐Ferreira¹,

Fontes‐Carvalho²,

Falcão-Pires³

et al. 2011

Arq. Bras. Cardiol.

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Titin is a giant sarcomeric protein that extends from the Z-line to the M-line. Due to its location, it represents an important biomechanical sensor, which has a crucial role in the maintenance of the sarcomere structural integrity. Titin works as a "bidireactional spring" that regulates the sarcomeric length and performs adequate adjustments of passive tension whenever the length varies. Therefore, it determines not only ventricular rigidity and diastolic function, but also systolic cardiac function, modulating the Frank-Starling mechanism.The myocardium expresses two isoforms of this macromolecule: the N2B, more rigid and the isoform N2BA, more compliant. The alterations in the relative expression of the two titin isoforms or alterations in their state of phosphorylation have been implicated in the pathophysiology of several diseases, such as diastolic heart failure, dilated cardiomyopathy, ischemic cardiomyopathy and aortic stenosis.The aim of this study is to describe, in brief, the structure and location of titin, its association with different cardiomyopathies and understand how alterations in this macromolecule influence the pathophysiology of diastolic heart failure, emphasizing the therapeutic potential of the manipulation of this macromolecule.

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Titin isoform expression in aortic stenosis

Cited by 36 publications

References 25 publications

A change of heart: oxidative stress in governing muscle function?

A change of heart: oxidative stress in governing muscle function?

Gigantic Business

Papel da titina na modulação da função cardíaca e suas implicações fisiopatológicas

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