Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy

Maniu, Calin V.; Krysiak, Judith; Shapiro, Brian P.; Meyer, Donna; Linke, Wolfgang A.; Redfield, Margaret M.

doi:10.1161/circheartfailure.108.768465

Cited by 32 publications

(27 citation statements)

References 45 publications

(81 reference statements)

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“…11 The time span over which LVEDWS rises is probably an important determinant for shifts in titin isoform expression because 2 canine dilated cardiomyopathy models with rapid elevation of LVEDWS induced by pacing tachycardia or by intracoronary microembolizations revealed an opposite shift with overexpression of the stiff N2B titin isoform. [25][26][27] Furthermore, the correlation observed in the present study between N2BA/N2B ratio and LVEDWS is also consistent with stress-sensing abilities of titin. Stress-sensing abilities of titin reside both in its kinase domain at the M-line 28 and in the titin/Tcap/muscle LIM protein complex at the Z-disc.…”

Section: Titin Isoform Expressionsupporting

confidence: 90%

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

Borbély

Falcão-Pires

Heerebeek

et al. 2009

Circulation Research

317

281

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Abstract-High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension (F passive ) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise F passive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related F passive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-m sarcomere length to measure F passive . Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. F passive was higher in HF (6.1Ϯ0.4 kN/m 2 ) than in CON (2.3Ϯ0.3 kN/m 2 ; PϽ0.01) or in AS (2.2Ϯ0.2 kN/m 2 ; PϽ0.001). Titin isoform expression differed between HF (N2BA/N2Bϭ0.73Ϯ0.06) and CON (N2BA/N2Bϭ0.39Ϯ0.05; PϽ0.001) and was comparable in HF and AS (N2BA/N2Bϭ0.59Ϯ0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2Bϭ0.77Ϯ0.05) than in AS (P-N2BA/P-N2Bϭ0.54Ϯ0.05; PϽ0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised

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Section: Titin Isoform Expressionsupporting

confidence: 90%

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

Borbély

Falcão-Pires

Heerebeek

et al. 2009

Circulation Research

317

281

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“…19 Moreover, increased myocyte tension, which can be prevented by experimental phosphorylation of titin, contributes to diastolic dysfunction in patients with severe HFNEF. 20,30 Additional modulatory effects on titin stiffness may arise from disulfide bonding under oxidant stress also affecting LV compliance. 31 Nevertheless, the steep part of the diastolic pressure-volume relation is mainly modified by the ECM, as can be observed when comparing stretch lengths between whole-muscle stripes and single myocytes, 32 suggesting that excess collagen might further aggravate diastolic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction

Westermann

Lindner

Kasner

et al. 2011

Circ: Heart Failure

529

378

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Background-The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results-We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-␤. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-␤, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-␤ resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. Conclusions-Cardiac

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“…118 A reduced N2BA:N2B expression ratio was also seen in tachypaced dog hearts. 119,120 Taken together, eccentric remodeled hearts with systolic dysfunction (DCM/HFrEF/chronic ischemic cardiomyopathy) frequently seem to express higher N2BA proportions than healthy hearts ( Figure 5A), thereby reducing myofibrillar passive stiffness ( Figure 5B). An exception is the tachypaced dog HF model, which increases the proportion of stiff N2B titin.…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 98%

“…An exception is the tachypaced dog HF model, which increases the proportion of stiff N2B titin. 119,120 Patients with HFpEF also express increased N2BA:N2B ratios, which lower titin-based stiffness. In contrast, characteristic for concentric remodeled hearts (compensated hypertrophy) with diastolic dysfunction following from hypertensive heart disease may be a decreased N2BA:N2B ratio causing elevated myocyte stiffness ( Figure 5A and 5B).…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

Self Cite

287

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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Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy

Cited by 32 publications

References 45 publications

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction

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