Modulation of Titin-Based Stiffness by Disulfide Bonding in the Cardiac Titin N2-B Unique Sequence

Grützner, Anika; Garcia-Manyes, Sergi; Kötter, Sebastian; Badilla, Carmen L.; Fernández, Julio M.; Linke, Wolfgang A.

doi:10.1016/j.bpj.2009.05.037

Cited by 156 publications

(147 citation statements)

References 55 publications

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“…Furthermore, cardiac-specific regions in titin are vulnerable to intramolecular disulfide bonding, which could stiffen the titin springs under oxidative stress conditions. 16 These recent findings complement earlier studies of ischemic and failing human hearts, which showed that titin is degraded 17 and appears highly disorganized in the cardiomyocytes when analyzed by immunofluorescence microscopy. 18 Taken together, evidence for titin alterations in human heart disease is manifold; derangement of titin in cardiac myocytes and reduced titin expression are obvious.…”

Section: Titin Functions and Alterations In Humansupporting

confidence: 85%

Molecular Giant Vulnerable to Oxidative Damage

Linke

2010

Circulation

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M atrix metalloproteinases (MMPs) are a family of Ͼ20 enzymes that have long puzzled scientists for their diversity in tissue location and function. True to their name, MMPs are best known for their role as degradation enzymes cleaving multiple components of the extracellular matrix, including collagen, laminin, elastin, and fibronectin. However, the traditional view that MMPs are proteases whose only function is to target matrix proteins does not hold up anymore. A large body of evidence suggests that the proteolysis of extracellular matrix scaffold proteins causes release of growth factors and other bioactive molecules, indicating that MMPs are involved in the regulation of cell and tissue function. 1 Moreover, recent proteomic screens for MMP substrates have shown that MMPs regulate a host of signaling molecules, such as chemokines, both directly and indirectly. 2 The novel functions of MMPs are also crucial to the cardiovascular system. MMP enzymes can regulate, for instance, the bioavailability of vascular endothelial growth factor and the potent vasodilator adrenomedullin. 2 The diverse roles of MMPs are relevant not only for physiological processes such as heart development but also for pathological processes such as remodeling events resulting from myocardial infarction, hypertensive heart disease, or cardiomyopathy. 3

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Section: Titin Functions and Alterations In Humansupporting

confidence: 85%

Molecular Giant Vulnerable to Oxidative Damage

Linke

2010

Circulation

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“…Oxidative stress leads to formation of disulfide bridges within the titin molecule, which raises its overall stiffness. 27 In a mouse HFPEF model, oxidative stress uncouples cardiac NOS and induces diastolic LV dysfunction. 28 Finally, high plasma levels of methylated L-arginine metabolites were strongly related to diastolic LV dysfunction in patients with HFREF.…”

Section: Pkg Activity and Myocardial Diastolic Dysfunction In Hfpefmentioning

confidence: 99%

Low Myocardial Protein Kinase G Activity in Heart Failure With Preserved Ejection Fraction

Hamdani²,

et al. 2012

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Background-Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F passive ) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F passive and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF). Methods and Results-Patients with HFPEF (nϭ36), AS (nϭ67), and HFREF (nϭ43) were free of coronary artery disease. More HFPEF patients were obese (PϽ0.05) or had diabetes mellitus (PϽ0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F passive was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (PϽ0.01) or HFREF (PϽ0.001) was associated with higher cardiomyocyte F passive (PϽ0.001) and related to lower cGMP concentration (PϽ0.001) and higher nitrosative/oxidative stress (PϽ0.05). Higher F passive in HFPEF was corrected by in vitro PKG administration. Conclusions-Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F passive and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment. (Circulation. 2012;126:830-839.)

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“…70 Disulfide bridge formation in the cardiac-specific N2-B segment of titin increases muscle passive stiffness, an effect reversible by Trx. 71 Increased atrial oxidative stress is involved in the pathophysiology of experimental and clinical atrial fibrillation (AF), and Nox2 is implicated in this process. Nox2-derived ROS production was increased in right atrial appendages of patients undergoing cardiac bypass surgery who developed postoperative AF 72 and was independently associated with increased AF risk.…”

Section: Abnormal Ca Regulation Contractile Dysfunction and Arrhythmiamentioning

confidence: 99%

Redox Signaling in Cardiac Physiology and Pathology

Burgoyne

Mongue‐Din

Eaton

et al. 2012

Circulation Research

426

365

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T he concept that oxidative stress-a pathologically high level of oxidant species in cells-may drive cardiovascular disease progression has led to many clinical trials of interventions, such as antioxidant vitamins. These, however, failed to show efficacy in reducing disease risk and progression. Part of the reason may be the focus on oxidative stress as detrimental neglected the wider role of redox balance and reactive oxygen species (ROS) and reactive nitrogen species in cellular (patho)physiology. Redox signaling-defined as the specific, usually reversible, oxidation/reduction modification of cellular signaling pathway components by a reactive species 1 -is increasingly appreciated as centrally important in many physiological and pathological processes. The main ROS involved in redox signaling are the superoxide anion (O 2 − ) and the more stable nonradical hydrogen peroxide (H 2 O 2 ) to which it dismutates, whereas more powerful oxidants such as hydroxyl are so reactive they are unlikely to be specific or reversible. Redox signaling also involves reactive nitrogen species such as NO and peroxynitrite, the latter being formed from the reaction of O 2 − with NO. 2In the heart, redox signaling is involved in physiological processes (eg, excitation-contraction coupling [ECC], cell differentiation), homoeostatic and stress response pathways (eg, adaptation to hypoxia/ischemia), and pathology (eg, adverse cardiac remodeling, fibrosis). This review covers recent advances in understanding the regulation of production of signaling ROS, their mechanisms of action and molecular targets in cardiac cells, and their involvement in cardiac physiopathology. We focus mainly on cardiomyocytes but redox signaling in other cells (eg, fibroblasts, endothelial cells), and functional cross talks among these are also important. Reactive nitrogen species-dependent regulation has been reviewed elsewhere. 2 ROS SourcesROS are generated as a by-product of cellular respiration and metabolism or by specialized enzymes that seem to be centrally involved in redox signaling. The signaling effects of ROS are influenced by their site of production, precise species, local concentration, and cell compartment-specific antioxidant pools. Major ROS sources in the heart and other tissues include the mitochondrial electron transport chain (ETC), other mitochondrial and metabolic enzymes, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs), and uncoupled NO synthases (NOS). Mitochondrial ETCElectron leakage from the ETC causes 1-electron reduction of O 2 to O 2 − (instead of reduction to H 2 O). Although considered to be because of an electron leak, such ROS may nevertheless contribute to homeostatic redox signals. ROS levels increase significantly during mitochondrial dysfunction. They can trigger the mitochondrial permeability transition (MPT) and lead to further ROS release-termed ROS-induced ROS release 3 -which propagates and amplifies ROS production and effects. ROS from non-ETC sources (eg, Noxs) may also stimulate ETC-depende...

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Modulation of Titin-Based Stiffness by Disulfide Bonding in the Cardiac Titin N2-B Unique Sequence

Cited by 156 publications

References 55 publications

Molecular Giant Vulnerable to Oxidative Damage

Molecular Giant Vulnerable to Oxidative Damage

Low Myocardial Protein Kinase G Activity in Heart Failure With Preserved Ejection Fraction

Redox Signaling in Cardiac Physiology and Pathology

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