Elastic titin properties and protein quality control in the aging heart

Salcan, Senem; Bongardt, Sabine; Barbosa, David; Efimov, Igor R.; Rassaf, Tienush; Kötter, Sebastian

doi:10.1016/j.bbamcr.2019.118532

Cited by 17 publications

(11 citation statements)

References 58 publications

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“…This may occur through an age-dependent effect on adaptive capacity that is distinct to the changes in titin isoform expression seen in heart failure. 41 Common variants in TTN were also implicated in ECG age-delta suggesting a shared genetic mechanism with conduction-associated traits. Using WES we found rare variants in two further genes that were were associated with deviation from healthy cardiovascular ageing.…”

Section: Discussionmentioning

confidence: 99%

Environmental and genetic predictors of human cardiovascular ageing

Shah

Inácio

et al. 2022

Preprint

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Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we used machine learning approaches to quantify cardiovascular ageing from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing was found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identified prescribed medications that were potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes.

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Section: Discussionmentioning

confidence: 99%

Environmental and genetic predictors of human cardiovascular ageing

Shah

Inácio

et al. 2022

Preprint

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“…In addition, titin and obscurin contain signaling domains close to their C-terminal (a protein serine/threonine kinase domain in titin, and a Rho-GTPase GTP-GDP exchange factor domain in obscurin) that can be coupled to two serine/threonine protein kinase domains [32]. Phosphorylation of a speci c sequence in the cardiac isoform (N2B region) by cAMP-dependent or cGMP-dependent protein kinases results in acute reduction in stiffness [33]. Based on the gene chip analysis, we identi ed that nearly 70% of mutations were related to TTN and nearly 40% of mutations were related to OBSCN.…”

Section: Discussionmentioning

confidence: 99%

Genomic and RNA-Seq Profiling of Patients with Heart Failure Identified Alterations in Phosphorylation and Immune Signaling Pathways

Zhang¹,

Li²,

Xu³

et al. 2021

Preprint

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Background: Heart failure (HF) is a complex pathophysiological state in which the delivery of blood and nutrients to the tissues is inadequate. It is rarely curable and often associated with poor prognosis. The current study aimed to analyze the exomic and RNA-Seq data of patients with HF to identify the key altered pathways. Methods: Heart failure participants were recruited, and whole blood samples were collected. The samples were used for whole exome sequencing and RNA-Seq analysis. Gene expression and RNA-Seq results were verified by Gene chips and RT-PCRResults: We report a dysregulation of phosphorylation and immune signaling in patients with HF both by exomic and RNA-Seq data. We identified mutations in TITIN,OBSCURIN, NOD2, CDH2, MAP3K5, and SLC17A4 to be associated with HF by exomic analysis. And certain genes, S100A12, S100A8, S100A9, PFDN5, and TMCC2, were found upregulated in patients with HF by RNA-Seq. Conlcusion: Our results demonstrated the overall disruption of key phosphorylation and immune signaling pathways in patients with HF.

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“…Interestingly, a recent study determined that in male mice or humans, titin isoforms were not altered with age. However, phosphorylation at specific sites on titin were differentially modified in male mice [ 61 ] . Similarly, phosphorylation of serine 44 of cardiac troponin I is elevated, and contractile function decreased in aging rats [ 57 ] .…”

Section: Cardiac Aging In Men and Womenmentioning

confidence: 99%

Mechanisms and implications of sex differences in cardiac aging

Yusifov¹,

Woulfe²,

Bruns³

2022

JCA

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Aging promotes structural and functional remodeling of the heart, even in the absence of external factors. There is growing clinical and experimental evidence supporting the existence of sex-specific patterns of cardiac aging, and in some cases, these sex differences emerge early in life. Despite efforts to identify sex-specific differences in cardiac aging, understanding how these differences are established and regulated remains limited. In addition to contributing to sex differences in age-related heart disease, sex differences also appear to underlie differential responses to cardiac stress such as adrenergic activation. Identifying the underlying mechanisms of sex-specific differences may facilitate the characterization of underlying heart disease phenotypes, with the ultimate goal of utilizing sex-specific therapeutic approaches for cardiac disease. The purpose of this review is to discuss the mechanisms and implications of sex-specific cardiac aging, how these changes render the heart more susceptible to disease, and how we can target age- and sex-specific differences to advance therapies for both male and female patients.

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Elastic titin properties and protein quality control in the aging heart

Cited by 17 publications

References 58 publications

Environmental and genetic predictors of human cardiovascular ageing

Environmental and genetic predictors of human cardiovascular ageing

Genomic and RNA-Seq Profiling of Patients with Heart Failure Identified Alterations in Phosphorylation and Immune Signaling Pathways

Mechanisms and implications of sex differences in cardiac aging

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