Molecular and structural transition mechanisms in long‐term volume overload

Mohamed, Belal A.; Schnelle, Moritz; Khadjeh, Sara; Lbik, Dawid; Herwig, Melissa; Linke, Wolfgang A.; Hasenfuß, Gerd; Toischer, Karl

doi:10.1002/ejhf.465

Cited by 58 publications

(80 citation statements)

References 31 publications

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“…Shunt increased cardiomyocyte width and length comparably (20% vs. 18%, and 24% vs. 25%, respectively) in WT versus D2 mice (Supplemental Figure 6). The degree of fibrosis, the expression of BNP, and the activation of signaling pathways are quite different in the Shunt model compared with the TAC model (13,33). Although shunt surgery is known to induce significant volume overload, CCND2 expression did not impact either cardiac function or survival.…”

Section: Discussionmentioning

confidence: 91%

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

Toischer

Zhu

Hünlich

et al. 2017

Journal of Clinical Investigation

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and ClueGO (54) and significantly regulated genes (cutoff adjusted P value < 0.05) of the transcriptomes of D2-TAC mice compared with D2-Shunt mice. The analysis is based on the following databases: GO biological function, GO cellular component, GO immune system process, GO molecular function, KEGG, REACTOME, and WikiPathways using GO Term Fusion and showing pathways with a P value of less than 0.05, a Kappa score of 0.4, and a minimum of 20 genes representing at least 5% of all genes of the pathway.Statistics. Results are expressed as mean ± SEM. Survival was tested with the log-rank (Mantel-Cox) test. Multiple group comparisons were performed by 2-way analysis of variance (ANOVA) followed by the Bonferroni procedure for comparison of means. Comparisons between 2 groups were performed using the unpaired 2-tailed Student's t test. All tests were 2-sided. Data were considered statistically significant at P less than 0.05.Study approval. The investigation conformed to the Guide for the Care and Use of Laboratory Animals (NIH publication number 85-23, revised 1996). The study was approved by the Lower Saxony State Office for Consumer Protection and Food Safety (G64/08 and 15/1860).

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Section: Discussionmentioning

confidence: 91%

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

Toischer

Zhu

Hünlich

et al. 2017

Journal of Clinical Investigation

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“…In contrast, no change in S4010 phosphorylation appeared in other mouse and rat HFpEF models . PKG‐dependent phosphosite S4099 was also found to be hypophosphorylated in most animal studies except for a mouse I/R model and a rat HFpEF model , where S4099 phosphorylation was unchanged. One study on a rat TAC model measured the phosphorylation of CaMKIIδ‐dependent phosphosite S4062, which was unchanged .…”

Section: Phosphorylation Of the Titin Spring In Normal And Failing Hementioning

confidence: 88%

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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“…However, eccentric hypertrophy can also occur in HFpEF patients, indicating a distinct subgroup of patients that may progress to HFrEF (117). In HFpEF clinical settings, as opposed to many experimental models, the transition to HFrEF is rarely observed (97) but, when it takes place, this transition is due to loss of contractile function within the remaining cardiomyocytes during LV remodeling, which is in line with distinct signaling pathways between HFpEF and HFrEF (97,171).…”

Section: Myocardial Remodelingmentioning

confidence: 88%

“…Also, an animal model of HFrEF induced by volume overload presented decrease levels of titin phosphorylation. In this case, the hypophosphorylation of titin represented a compensatory mechanism to the lack of cardiac interstitial fibrosis and cardiomyocytes loss in disease animals (171).…”

Section: Myocardial Remodelingmentioning

confidence: 98%

Myocardial reverse remodeling: how far can we rewind?

Gonçalves-Rodrigues

Leite‐Moreira

Falcão-Pires

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions.

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Molecular and structural transition mechanisms in long‐term volume overload

Cited by 58 publications

References 31 publications

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

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

Myocardial reverse remodeling: how far can we rewind?

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