Stretch-induced compliance: a novel adaptive biological mechanism following acute cardiac load

Leite-Moreira, André M.; Almeida-Coelho, João; Neves, João Sérgio; Pires, Ana; Ferreira-Martins, João; Castro‐Ferreira, Ricardo; Ladeiras-Lopes, Ricardo; Conceição, Glória; Miranda-Silva, Daniela; Gonçalves-Rodrigues, Patrícia; Hamdani, Nazha; Herwig, Melissa; Falcão-Pires, Inês; Paulus, Walter J.; Linke, Wolfgang A.; Lourenço, André P.; Leite‐Moreira, Adelino

doi:10.1093/cvr/cvy026

Cited by 18 publications

(18 citation statements)

References 40 publications

(38 reference statements)

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“…Finally, PTMs of titin that alter titin‐based myocardial passive stiffness represent a promising potential target for therapeutic intervention in HF patients with overly stiff hearts (such as in HFpEF), despite recent setbacks in some preclinical studies regarding to the role of cGMP‐PKG activation for myocardial stiffness in vivo . However, new approaches have already shown that titin phosphorylation and titin compliance can be increased in animal models by targeting various other intracellular pathways . Results of these studies suggest that the correction of mechanically relevant PTMs of titin in failing hearts can reduce pathological wall stiffness and normalize diastolic function.…”

Section: Discussionmentioning

confidence: 99%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including the sarcomeres of cardiomyocytes. The last decade has seen enormous progress in our understanding of how titin molecular elasticity is modulated in a dynamic manner to help cardiac sarcomeres adjust to the varying hemodynamic demands on the heart. Crucial events mediating the rapid modulation of cardiac titin stiffness are post‐translational modifications (PTMs) of titin. In this review, we first recollect what is known from earlier and recent work on the molecular mechanisms of titin extensibility and force generation. The main goal then is to provide a comprehensive overview of current insight into the relationship between titin PTMs and cardiomyocyte stiffness, notably the effect of oxidation and phosphorylation of titin spring segments on titin stiffness. A synopsis is given of which type of oxidative titin modification can cause which effect on titin stiffness. A large part of the review then covers the mechanically relevant phosphorylation sites in titin, their location along the elastic segment, and the protein kinases and phosphatases known to target these sites. We also include a detailed coverage of the complex changes in phosphorylation at specific titin residues, which have been reported in both animal models of heart disease and in human heart failure, and their correlation with titin‐based stiffness alterations. Knowledge of the relationship between titin PTMs and titin elasticity can be exploited in the search for therapeutic approaches aimed at softening the pathologically stiffened myocardium in heart failure patients.

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Section: Discussionmentioning

confidence: 99%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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“…In isolated rabbit cardiac muscle strips, pharmacological inhibition of NO signaling did not affect the decrease of passive tension in response to acute stretch. In contrast, this response was significantly reduced by blocking the actions of both NO and natriuretic peptides, an effect comparable to PKGI inhibition (14). Furthermore, in vivo, pharmacological activation of soluble guanylate cyclase did not influence ventricular compliance in normal and hypertrophied porcine hearts (15).…”

Section: Introductionmentioning

confidence: 91%

C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

et al. 2020

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“…Titin is a mediator for mechano-sensory processes due to its ability to form multiple protein-protein interactions throughout the sarcomere (Kruger and Linke, 2009). The function of titin on passive tension is mediated by cyclic GMP-dependent PKG-mediated phosphorylation of several sites within the spring region of titin Leite-Moreira et al, 2018). PKG-mediated phosphorylation of titin at serine residue S469 alters the elasticity of N2B-unique sequence of titin, leading to reduced passive tension in human donor non-failing cardiac fibers .…”

Section: Titinmentioning

confidence: 99%

Nitric Oxide and Mechano-Electrical Transduction in Cardiomyocytes

et al. 2020

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The ability§ of the heart to adapt to changes in the mechanical environment is critical for normal cardiac physiology. The role of nitric oxide is increasingly recognized as a mediator of mechanical signaling. Produced in the heart by nitric oxide synthases, nitric oxide affects almost all mechano-transduction pathways within the cardiomyocyte, with roles mediating mechano-sensing, mechano-electric feedback (via modulation of ion channel activity), and calcium handling. As more precise experimental techniques for applying mechanical stresses to cells are developed, the role of these forces in cardiomyocyte function can be further understood. Furthermore, specific inhibitors of different nitric oxide synthase isoforms are now available to elucidate the role of these enzymes in mediating mechano-electrical signaling. Understanding of the links between nitric oxide production and mechano-electrical signaling is incomplete, particularly whether mechanically sensitive ion channels are regulated by nitric oxide, and how this affects the cardiac action potential. This is of particular relevance to conditions such as atrial fibrillation and heart failure, in which nitric oxide production is reduced. Dysfunction of the nitric oxide/mechano-electrical signaling pathways are likely to be a feature of cardiac pathology (e.g., atrial fibrillation, cardiomyopathy, and heart failure) and a better understanding of the importance of nitric oxide signaling and its links to mechanical regulation of heart function may advance our understanding of these conditions.

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Stretch-induced compliance: a novel adaptive biological mechanism following acute cardiac load

Abstract: We describe and translate to human physiology a novel adaptive mechanism, partly mediated by titin phosphorylation through cGMP-PKG signalling, whereby myocardial compliance increases in response to acute stretching. This mechanism may not function in the hypertrophic heart.

Cited by 18 publications

References 40 publications

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

Nitric Oxide and Mechano-Electrical Transduction in Cardiomyocytes

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