Activin-A, Transforming Growth Factor-β, and Myostatin Signaling Pathway in Experimental Dilated Cardiomyopathy

Mahmoudabady, Maryam; Maisonneuve, Mathieu; Dewachter, Laurence; Hadad, Ielham; Ray, Lynn; Jespers, Pascale; Brimioulle, Serge; Naeije, Robert; McEntee, Kathleen

doi:10.1016/j.cardfail.2008.05.003

Cited by 26 publications

(16 citation statements)

References 30 publications

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“…In vitro studies in isolated cardiomyocytes suggest that myostatin mRNA and protein can be directly induced in these cells by mechanical stretch or humoral stimulation with IGF-I, phenylephrine, or angiotensin II, involving intracellular activation of mitogen-activated protein kinases (p38 and/or ERK) and binding of the transcription factor MEF2 within the myostatin promoter region (15,74,87). One study failed to report an enhancement of cardiac myostatin mRNA during heart failure progression in dogs due to overpacing but instead detected elevated levels of the related activin-A in moderate and severe heart failure (2-to 3-fold increase) (47). The cause for the deviant result in this study might be that myocardial samples were obtained by biopsy from the septal region within the right ventricle, which reportedly has lower myostatin levels and which is also exposed to different loading conditions compared with the left ventricle.…”

Section: Cardiac Myostatin In Health and Diseasementioning

confidence: 99%

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Breitbart

Auger‐Messier

Molkentin

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

104

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A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future.

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Section: Cardiac Myostatin In Health and Diseasementioning

confidence: 99%

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Breitbart

Auger‐Messier

Molkentin

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

104

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“…There is decreased attachment to laminin, fi bronectin, and type IV collagen, leading to focal disruptions of the basement membrane/sarcolemmal interfaces and a reduced number of sarcolemmal festoons [22,23]. The transforming growth factor-β-activin-A/Smad signaling pathway and their target gene p21 may be involved [24]. Highenergy stores are depleted, related to increased cellular metabolism and mitochondrial injury [5,25].…”

Section: Pathophysiologymentioning

confidence: 99%

Tachycardia-mediated cardiomyopathy: Recognition and management

Gopinathannair¹,

Sullivan²,

Olshansky

2009

Curr Heart Fail Rep

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Tachycardia-mediated cardiomyopathy is a cause of ventricular dysfunction due to, at least partially, persistent tachycardia leading to cellular and extracellular perturbations. Cardiomyopathy may take years to develop, but pharmacologic management to achieve rate control and reverse remodeling, as well as cardioversion or ablative strategies to stop the tachycardia, can result in rapid recovery from symptoms and gradual improvement in left ventricular ejection fraction. However, ultrastructural changes can remain and may lead to a rapid decline in ventricular function if tachycardia recurs. Ultrastructural changes may also explain a propensity toward sudden death even if the ejection fraction normalizes. Although the etiology, pathophysiology, and late clinical manifestations of tachycardia-mediated cardiomyopathy are beginning to be understood, investigation continues, focusing on prevention, early recognition, and acute and long-term management in an attempt to lessen heart failure and prevent risk of sudden death.

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“…Accumulating evidence from gene profiling and other studies implicates diverse pathways, including among others, the vascular renin–angiotensin system [15], G i -coupled receptors [16], TGFβ-activin-A/Smad signaling pathway [17], SH2-containing cytoplasmic tyrosine phosphatase (Shp) [18] and apoptotic signaling [15,17–20], to name a few. While classical opinion might argue that several of these alterations occur independently of the underlying etiology of the disease, it has also become apparent that the greater part of the familiar myocardial changes is probably triggered by chronic neurohumoral activation and abnormal mechanical load [21], which greatly promote the progression of heart failure as part of a vicious circle.…”

Section: Introductionmentioning

confidence: 99%

Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

et al. 2009

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We employed ABI high-density oligonucleotide microarrays containing 31,700 sixty-mer probes (representing 27,868 annotated human genes) to determine differential gene expression in idiopathic dilated cardiomyopathy (DCM). We identified 626 up-regulated and 636 down-regulated genes in DCM compared to controls. Most significant changes occurred in the tricarboxylic acid cycle, angiogenesis, and apoptotic signaling pathways, among which 32 apoptosis- and 13 MAPK activity-related genes were altered. Inorganic cation transporter, catalytic activities, energy metabolism and electron transport-related processes were among the most critically influenced pathways. Among the up-regulated genes were HTRA1 (6.9-fold), PDCD8(AIFM1) (5.2) and PRDX2 (4.4) and the down-regulated genes were NR4A2 (4.8), MX1 (4.3), LGALS9 (4), IFNA13 (4), UNC5D (3.6) and HDAC2 (3) (pb0.05), all of which have no clearly defined cardiac-related function yet. Gene ontology and enrichment analysis also revealed significant alterations in mitochondrial oxidative phosphorylation, metabolism and Alzheimer’s disease pathways. Concordance was also confirmed for a significant number of genes and pathways in an independent validation microarray dataset. Furthermore, verification by real-time RT-PCR showed a high degree of consistency with the microarray results. Our data demonstrate an association of DCM with alterations in various cellular events and multiple yet undeciphered genes that may contribute to heart muscle disease pathways.

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Activin-A, Transforming Growth Factor-β, and Myostatin Signaling Pathway in Experimental Dilated Cardiomyopathy

Cited by 26 publications

References 30 publications

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Tachycardia-mediated cardiomyopathy: Recognition and management

Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

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