More severe cellular phenotype in human idiopathic dilated cardiomyopathy compared to ischemic heart disease

Hamdani, Nazha; Borbély, Attila; Veenstra, Sophie P. G. R.; Kooij, Viola; Vrydag, Wim; Zaremba, R.; Remedios, Cris dos; Niessen, Hans W.M.; Michel, Martin C.; Paulus, Walter J.; Stienen, G. J. M.; Velden, Jolanda van der

doi:10.1007/s10974-010-9231-8

Cited by 37 publications

(46 citation statements)

References 43 publications

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“…Regression analysis showed that pCa 50 values for the non-failing preparations were negatively correlated with both total cMyBP-C phosphorylation (p=0.002, Figure S8A) and Ser302 phosphorylation (p=0.045, Figure S8B). The former finding reinforces data from a previous study using myocardial samples from unspecified regions of human hearts [14] but the new link between phosphorylation of cMyBP-C at Ser302 and pCa 50 is a novel finding.…”

Section: Region-specific Modification In Ca 2+ Sensitivitysupporting

confidence: 88%

“…For example, separate studies using epicardial biopsies [10] and samples from unspecified regions of the heart [11] have shown that isometric force is reduced by ~80% in patients with heart failure. Other works, using samples from unspecified regions of the left ventricle, suggests that there is no significant effect of heart failure on maximum isometric force [12][13][14]. In the present experiments, heart failure reduced the average force generated by the experimental preparations (Figure 2, p=0.042).…”

Section: Region-specific Modifications In Systolic Functionsupporting

confidence: 46%

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Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

Haynes

Nava

Lawson

et al. 2014

The Journal of Heart and Lung Transplantation

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Section: Region-specific Modification In Ca 2+ Sensitivitysupporting

confidence: 88%

Section: Region-specific Modifications In Systolic Functionsupporting

confidence: 46%

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

Haynes

Nava

Lawson

et al. 2014

The Journal of Heart and Lung Transplantation

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“…MLCK3 was also identified as a HF-related gene. 34 Surprisingly, studies in mice have demonstrated that the ablation of MLCK3 attenuates MLC2 phosphorylation and no changes in tissue morphology occur. 35 These data suggest that another kinase could phosphorylate MLC and could participate in the structural and functional changes that occur during HF.…”

Section: Discussionmentioning

confidence: 99%

RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure

Herrer

Roselló‐Lletí

Rivera

et al. 2014

Laboratory Investigation

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Changes in cardiomyocyte cytoskeletal components, a crucial scaffold of cellular structure, have been found in heart failure (HF); however, the altered cytoskeletal network remains to be elucidated. This study investigated a new map of cytoskeleton-linked alterations that further explain the cardiomyocyte morphology and contraction disruption in HF. RNA-Sequencing (RNA-Seq) analysis was performed in 29 human LV tissue samples from ischemic cardiomyopathy (ICM; n ¼ 13) and dilated cardiomyopathy (DCM, n ¼ 10) patients undergoing cardiac transplantation and six healthy donors (control, CNT) and up to 16 ICM, 13 DCM and 7 CNT tissue samples for qRT-PCR. Gene Ontology analysis of RNA-Seq data demonstrated that cytoskeletal processes are altered in HF. We identified 60 differentially expressed cytoskeleton-related genes in ICM and 58 genes in DCM comparing with CNT, hierarchical clustering determined that shared cytoskeletal genes have a similar behavior in both pathologies. We further investigated MYLK4, RHOU, and ANKRD1 cytoskeletal components. qRT-PCR analysis revealed that MYLK4 was downregulated ( À 2.2-fold; Po0.05) and ANKRD1 was upregulated (2.3-fold; Po0.01) in ICM patients vs CNT. RHOU mRNA levels showed a statistical trend to decrease ( À 2.9-fold). In DCM vs CNT, MYLK4 ( À 4.0-fold; Po0.05) and RHOU ( À 3.9-fold; Po0.05) were downregulated and ANKRD1 (2.5-fold; Po0.05) was upregulated. Accordingly, MYLK4 and ANKRD1 protein levels were decreased and increased, respectively, in both diseases. Furthermore, ANKRD1 and RHOU mRNA levels were related with LV function (Po0.05). In summary, we have found a new map of changes in the ICM and DCM cardiomyocyte cytoskeleton. ANKRD1 and RHOU mRNA levels were related with LV function which emphasizes their relevance in HF. These new cytoskeletal changes may be responsible for altered contraction and cell architecture disruption in HF patients. Moreover, these results improve our knowledge on the role of cytoskeleton in functional and structural alterations in HF.

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“…This investigation conformed with the principles outlined in the Declaration of Helsinki (1997). The human cardiac samples have been extensively characterized (force characteristics and cTnI phosphorylation) in a previous study (13).…”

Section: Expression and Purification Of Recombinant Troponin Subunitsmentioning

confidence: 99%

“…This approach allowed us to study the effect of cTnI phosphorylation on active [maximal force (F max )] and passive isometric force (F pas ), the force-Ca 2ϩ relation, and the rate of force redevelopment (k tr ; a measure of cross-bridge kinetics). In addition, cardiomyocytes from idiopathic dilated cardiomyopathic (IDCM) tissue were used for titration of the effect of pseudo-bisphosphorylated cTnI as these cardiomyocytes have a low level of cTnI bisphosphorylation at baseline (13,41).…”

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confidence: 99%

Impact of site-specific phosphorylation of protein kinase A sites Ser²³and Ser²⁴of cardiac troponin I in human cardiomyocytes

Wijnker

Foster

Tsao

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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unphosphorylated, and cTnI-AA mimics both sites unphosphorylated. Force development was measured at various Ca 2ϩ concentrations in permeabilized cardiomyocytes in which the endogenous troponin complex was exchanged with these recombinant human troponin complexes. In donor cardiomyocytes, myofilament Ca 2ϩ sensitivity (pCa50) was significantly lower in cTnI-DD (pCa50: 5.39 Ϯ 0.01) compared with cTnI-AA (pCa50: 5.50 Ϯ 0.01), cTnI-AD (pCa50: 5.48 Ϯ 0.01), and cTnI-DA (pCa50: 5.51 Ϯ 0.01) at ϳ70% cTn exchange. No effects were observed on the rate of tension redevelopment. In cardiomyocytes from idiopathic dilated cardiomyopathic tissue, a linear decline in pCa50 with cTnI-DD content was observed, saturating at ϳ55% bisphosphorylation. Our data suggest that in the human myocardium, phosphorylation of both PKA sites on cTnI is required to reduce myofilament Ca 2ϩ sensitivity, which is maximal at ϳ55% bisphosphorylated cTnI. The implications for in vivo cardiac function in health and disease are detailed in the DISCUSSION in this article. myofilament function; protein phosphorylation; cardiomyocyte; troponin I DURING STRESS AND EXERCISE, sympathetic activation of the heart increases heart rate and stroke volume to meet the demands of the body. This is mediated via the stimulation of ␤ 1 -adrenergic receptors, which leads to the activation of a downstream kinase, PKA. PKA enhances cardiomyocyte contraction and relaxation by phosphorylation of proteins involved in Ca 2ϩ handling and myofilament proteins such as cardiac troponin (cTn)I, cardiac myosin-binding protein-C (cMyBP-C), and titin (for reviews, see Refs. 1 and 37).PKA-mediated phosphorylation of myofilament proteins is thought to exert a positive lusitropic effect, which enables the heart to relax more rapidly when heart rate increases. This positive lusitropic effect may be induced by a decrease in myofilament Ca 2ϩ sensitivity (32, 35, 51) and by enhanced cross-bridge cycling kinetics (11,20,33). It is well established (mainly from studies in rodents) that phosphorylation of cTnI at the PKA sites Ser 23 and Ser 24 leads to a decrease in myofilament Ca 2ϩ sensitivity, through a conformational change of the troponin complex. This structural change reduces the affinity of Ca 2ϩ binding to cTnC (16,30). The role of phosphorylation of cTnI at the PKA sites as a regulator of cross-bridge cycling is less clear. Some studies (11,20,36) have reported an increase in cross-bridge kinetics via phosphorylation of cTnI. However, others (7, 33) have attributed an increase in cross-bridge kinetics to phosphorylation of cMyBP-C independent of cTnI phosphorylation, whereas several studies (8,15,17,44) did not find an effect of PKA on cross-bridge kinetics at all. In the present study, we aimed to study the effect of site-specific phosphorylation of cTnI on myofilament Ca 2ϩ sensitivity and cross-bridge kinetics in human cardiomyocytes since insights into the functional effects of cTnI phosphorylation and the relation between the level of phosphorylation and the functional effec...

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More severe cellular phenotype in human idiopathic dilated cardiomyopathy compared to ischemic heart disease

Cited by 37 publications

References 43 publications

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure

Impact of site-specific phosphorylation of protein kinase A sites Ser²³and Ser²⁴of cardiac troponin I in human cardiomyocytes

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More severe cellular phenotype in human idiopathic dilated cardiomyopathy compared to ischemic heart disease

Cited by 37 publications

References 43 publications

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure

Impact of site-specific phosphorylation of protein kinase A sites Ser23and Ser24of cardiac troponin I in human cardiomyocytes

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Impact of site-specific phosphorylation of protein kinase A sites Ser²³and Ser²⁴of cardiac troponin I in human cardiomyocytes