Sarcomeric dysfunction in heart failure

Hamdani, Nazha; Kooij, Viola; Dijk, Sabine van; Merkus, Daphne; Paulus, Walter J.; Remedios, Cris dos; Duncker, Dirk J.; Stienen, G. J. M.; Velden, Jolanda van der

doi:10.1093/cvr/cvm079

Cited by 162 publications

(144 citation statements)

References 95 publications

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“…Excess production of reactive oxygen species (ROS) has been implicated in progression of chronic heart failure as well as in other cardiovascular disorders including ischemia-reperfusion injury and cardiovascular complications of hemolytic diseases [2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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Heart failure is a leading cause of morbidity and mortality in patients affected by different disorders associated to intravascular hemolysis. The leading factor is the presence of pathologic amount of pro-oxidant free heme in the bloodstream, due to the exhaustion of the natural heme scavenger Hemopexin (Hx). Here, we evaluated whether free heme directly affects cardiac function, and tested the therapeutic potential of replenishing serum Hx for increasing serum heme buffering capacity.The effect of heme on cardiac function was assessed in vitro, on primary cardiomyocytes and H9c2 myoblast cell line, and in vivo, in Hx -/-mice and in genetic and acquired mouse models of intravascular hemolysis. Purified Hx or anti-oxidants N-Acetyl-L-cysteine and α-tocopherol were used to counteract heme cardiotoxicity.In mice, Hx loss/depletion resulted in heme accumulation and enhanced reactive oxygen species (ROS) production in the heart, which ultimately led to severe systolic dysfunction. Similarly, high ROS reduced systolic Ca 2+ transient amplitudes and fractional shortening in primary cardiomyocytes exposed to free heme. In keeping with these Ca 2+ handling alterations, oxidation and CaMKIIdependent phosphorylation of Ryanodine Receptor 2 were higher in Hx -/-hearts than in controls.Administration of anti-oxidants prevented systolic failure both in vitro and in vivo. Intriguingly, Hx rescued contraction defects of heme-treated cardiomyocytes and preserved cardiac function in hemolytic mice.We show that heme-mediated oxidative stress perturbs cardiac Ca 2+ homeostasis and promotes contractile dysfunction. Scavenging heme, Hx counteracts cardiac heme toxicity and preserves left ventricular function. Our data generate the rationale to consider the therapeutic use of Hx to limit the cardiotoxicity of free heme in hemolytic disorders.

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Section: Introductionmentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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“…For example, in experimental heart failure in the rat, we found a depression in myofilament function that was causally linked to alterations in Tn; a follow-up study demonstrated that this was due to, most likely, up-regulation of PKC-α activity and the subsequent phosphorylation of cardiac contractile proteins [5,6]. Likewise, studies by van der Velden et al indicate that depressed myofilament function in human heart failure is associated with alterations in Tn phosphorylation, as well as other contractile proteins such as myosin light chain and myosin-binding protein C [27]. Thus, maladaptive contractile protein function, and in particular contractile protein phosphorylation, may be a worthy signaling mechanism to target so as to restore contractile function of the ventricular myocyte in end-stage CHF.…”

Section: Cardiac Diseasesmentioning

confidence: 99%

“…Although it is well recognized that disturbances in calcium regulation constitute an important mechanism in this process [7], it is now clear that heart failure is also associated with a decline in myofilament response to activator Ca 2+ [15,16,27,37,67,72]. Although isoform distribution and proteolytic cleavage of contractile proteins may play a role, (inappropriate) contractile protein phosphorylation has emerged as an important determinant of depressed myofilament function in various etiologies of heart failure [5,6,27,67]. For example, in experimental heart failure in the rat, we found a depression in myofilament function that was causally linked to alterations in Tn; a follow-up study demonstrated that this was due to, most likely, up-regulation of PKC-α activity and the subsequent phosphorylation of cardiac contractile proteins [5,6].…”

Section: Cardiac Diseasesmentioning

confidence: 99%

“…Recent investigations have provided new insights into the molecular mechanisms that underlie thin filament activation and the role of contractile protein phosphorylation in modulating myofilament function in the heart [37,67]. Moreover, contractile protein phosphorylation has emerged as an important determinant of depressed myofilament function in cardiac diseases such as the syndrome of congestive heart failure, cardiac hypertrophy, and diabetic cardiomyopathy [5,6,27,67]. Accordingly, this review is focused on the cardiac thin filament and its role in regulating cardiac myofilament dynamics both in health and disease.…”

Section: Introduction and Scopementioning

confidence: 99%

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Cardiac thin filament regulation

Kobayashi

Liu

Tombe

2008

Pflugers Arch - Eur J Physiol

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Myocardial contraction is initiated upon the release of calcium into the cytosol from the sarcoplasmic reticulum following membrane depolarization. The fundamental physiological role of the heart is to pump an amount blood that is determined by the prevailing requirements of the body. The physiological control systems employed to accomplish this task include regulation of heart rate, the amount of calcium release, and the response of the cardiac myofilaments to activator calcium ions. Thin filament activation and relaxation dynamics has emerged as a pivotal regulatory system tuning myofilament function to the beat-to-beat regulation of cardiac output. Maladaptation of thin filament dynamics, in addition to dysfunctional calcium cycling, is now recognized as an important cellular mechanism causing reduced cardiac pump function in a variety of cardiac diseases. Here, we review current knowledge regarding protein-protein interactions involved in the dynamics of thin filament activation and relaxation and the regulation of these processes by protein kinase-mediated phosphorylation.

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“…PKA mediated phosphorylation of titin results in decreased stiffness of the cardiac myofilament. This process may be physiologically significant as it was recently shown that myocytes obtained from patients with diastolic heart failure were less compliant than normal cells and treatment of the skinned myocytes with PKA reversed this abnormality [10].…”

mentioning

confidence: 99%

Some rat: A very special rat with a rather special titin

Cazorla¹,

Tombe²

2008

Journal of Molecular and Cellular Cardiology

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Cycling cross-bridges, the molecular interactions between the contractile proteins actin and myosin, generate the muscle force that underlies cardiac pressure development. In striated muscle, these proteins are organized in the thick and thin filaments that together form the sarcomere. A more recent discovery localizes a third filament to the sarcomere, one that is composed of titin. Titin, also known as connectin, is a giant protein (3-4 MDaltons) that is an abundant protein in striated muscle forming up to 10% of the total protein content of the cardiac cell. Titin extends half the length of the sarcomere from the Z-disc through the I-band and Aband on to the M-line (~1 μm). The molecule is tightly anchored at its NH 2 -terminus in the Zdisk via interactions with alpha-actinin and at its C-terminal domain to the M-line via interactions with myosin. The cell biology of titin has been the subject of intense study by several groups following its discovery in 1979 [1]. was immediately recognized that a significant function of titin in the sarcomere might be structural. Indeed, titin has emerged as the main cellular structure responsible for passive striated muscle cell stiffness [2,3]. Furthermore, within the physiological range of cardiac volume, titin appears to be responsible for a significant portion of the diastolic passive filling pressure of the heart; the remainder of the elastic force being generated by extracellular matrix collagen [4]. The elasticity of titin originates within the I-band portion due to the presence of i) tandem immunoglobulin (Ig) repeats, ii) a region rich in proline (P), glutamate (E), valine (V), and lysine (K), the PEVK region and iii) a region with a sequence unique to cardiac titin, the N2B region. Alternative splicing provides additional tandem Ig repeats that insert between the N2B and PEVK regions. These longer titin isoforms also have an N2A region and are termed N2BA. In a sarcomere at slack length, titin is highly folded with many of the regions acting as entropic springs. As the sarcomere is stretched, the links between the tandem Ig repeats extend first. As the stretch proceeds, the PEVK sequence unfolds and at the upper end of the physiological range of sarcomere lengths the N2B region also unfolds. Over the normal physiological range of sarcomere lengths and forces, the tandem Ig repeats are not thought to unfold, although these repeats can be made to unfold in isolated titin molecules [2,3].It has become increasingly clear recently that titin's functions are far more complex and that this giant molecule may play a much larger role in striated muscle physiology than merely as a passive stress bearing protein. For example, it has been suggested that titin plays an important

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Sarcomeric dysfunction in heart failure

Cited by 162 publications

References 95 publications

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Cardiac thin filament regulation

Some rat: A very special rat with a rather special titin

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