Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1

Hopf, A; Andresen, Christian; Kötter, Sebastian; Isić, Małgorzata; Ulrich, Kamila; Sahin, Senem; Bongardt, Sabine; Röll, Wilhelm; Drove, Felicitas; Scheerer, Nina; Vandekerckhove, Leni; Keulenaer, Gilles W. De; Hamdani, Nazha; Linke, Wolfgang A.; Krüger, Martina

doi:10.1161/circresaha.117.312166

Cited by 76 publications

(66 citation statements)

References 36 publications

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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%

“…). Specifically, phosphorylation of S11878 was increased in LV samples from patients with severe DCM , HCM , and HFpEF associated with HT or T2DM vs. the respective nonfailing controls. These changes were accompanied by an increase in titin‐based passive tension.…”

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

confidence: 94%

“…Specifically, mice exposed to TAC [102], I/R [110] or chronic volume overload [99], HT rats [104], and a canine model of HFpEF [108] all showed hyperphosphorylation of S11878. In contrast, different studies using murine models of I/R [93] and chronic volume overload [100], a rat TAC model [103], and both a murine and two rat models of HFpEF [101,106,111] revealed no change in phosphorylation at S11878.…”

Section: Pevk Site-specific Phosphorylationmentioning

confidence: 97%

“…). This observation was made in patients with severe forms of DCM , HCM , HFpEF associated with HT , HFpEF associated with T2DM , PAH , and PPCM . In contrast, some studies found that passive tension was unchanged in LV samples from patients with DCM or IDCM vs. donor hearts or even decreased at the level of the cardiac myofibrils .…”

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

confidence: 98%

“…PKA/ ERK2-dependent phosphosite S4010 was hypophosphorylated in mice exposed to I/R [110] or chronic volume overload [99], in rat TAC and HFpEF models [103,106], and in a dog HFpEF model [108]. In contrast, no change in S4010 phosphorylation appeared in other mouse and rat HFpEF models [101,111]. PKGdependent phosphosite S4099 was also found to be hypophosphorylated in most animal studies [99,103,108] except for a mouse I/R model [110] and a rat HFpEF model [111], where S4099 phosphorylation was unchanged.…”

Section: N2bus Site-specific Phosphorylationmentioning

confidence: 99%

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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: Phosphorylation Of the Titin Spring In Normal And Failing Hementioning

confidence: 88%

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

confidence: 94%

Section: Pevk Site-specific Phosphorylationmentioning

confidence: 97%

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

confidence: 98%

Section: N2bus Site-specific Phosphorylationmentioning

confidence: 99%

See 3 more Smart Citations

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

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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Expression of farnesyl pyrophosphate synthase is increased in diabetic cardiomyopathy

Zhang

Wang

Qiu

et al. 2021

Cell Biology International

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Farnesyl pyrophosphate synthase (FPPS)‐catalyzed isoprenoid intermediates are involved in diabetic cardiomyopathy. This study investigated the specific role of FPPS in the development of diabetic cardiomyopathy. We demonstrated that FPPS expression was elevated in both in vivo and in vitro models of diabetic cardiomyopathy. FPPS inhibition decreased the expression of proteins related to cardiac fibrosis and cardiomyocytic hypertrophy, including collagen I, collagen III, connective tissue growth factor, natriuretic factor, brain natriuretic peptide, and β‐myosin heavy chain. Furthermore, FPPS inhibition and knockdown prevented phosphorylated c‐Jun N‐terminal kinase 1/2 (JNK1/2) activation in vitro. In addition, a JNK1/2 inhibitor downregulated high‐glucose‐induced responses to diabetic cardiomyopathy. Finally, immunofluorescence revealed that cardiomyocytic size was elevated by high glucose and was decreased by zoledronate, small‐interfering farnesyl pyrophosphate synthase (siFPPS), and a JNK1/2 inhibitor. Taken together, our findings indicate that FPPS and JNK1/2 may be part of a signaling pathway that plays an important role in diabetic cardiomyopathy.

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Circulating neuregulin1‐β in heart failure with preserved and reduced left ventricular ejection fraction

et al. 2020

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Aims Neuregulin1-β (NRG1-β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). Methods and results Circulating NRG1-β was quantified in 86 stable patients with HFpEF (EF ≥45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-β and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th-75th percentile) NRG1-β was 6.5 (2.1-11.3) ng/mL; in HFrEF, 3.6 (2.1-7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9-3.6) ng/mL; after HTx 2.1 (1.4-3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1-34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04-2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-β with outcomes was modified by ischaemia (log-rank P = 0.020; P interaction = 0.553) such that only in ischaemic patients, higher NRG1-β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085). Conclusions Neuregulin1-β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-β with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-β from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

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Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1

Cited by 76 publications

References 36 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?

Expression of farnesyl pyrophosphate synthase is increased in diabetic cardiomyopathy

Circulating neuregulin1‐β in heart failure with preserved and reduced left ventricular ejection fraction

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