Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Brody, Matthew J.; Vanhoutte, Davy; Schips, Tobias G.; Boyer, Justin G.; Bakshi, Chinmay V.; Sargent, Michelle A.; York, Allen J.; Molkentin, Jeffery D.

doi:10.1128/mcb.00114-18

Cited by 24 publications

(18 citation statements)

References 55 publications

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“…Dysferlin, MG53, and thrombospondin 4 (Thbs4) have been identified as important players in membrane repair and maintenance. Ablation of any of these genes in dystrophin-null or sarcoglycan-null animals has been shown to worsen their cardiac and skeletal muscle pathology [34,35,36,37,38]. In fact, primary dysferlin deficiency is associated with muscular dystrophy in animal models and human patients (Miyoshi Myopathy and LGMD2B) characterized by mild-moderate muscle weakness and infrequent cardiac dysfunction [39].…”

Section: Pathophysiological Mechanisms Of Dystrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers

Townsend

2019

IJMS

107

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Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.

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Section: Pathophysiological Mechanisms Of Dystrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers

Townsend

2019

IJMS

107

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“…While TSP-4 is best known as a secreted extracellular matrix (ECM) protein, it became clear that some of its effects depend on its intracellular interactions: its binding to the ER lumenal domain of activating transcription factor 6α (Atf6α) protects cardiomyocytes from injury caused by ER stress responses 7 . Thus, this protein exerts its effect in multiple complementary ways: by initiating intracellular signaling and transiting through secretory pathways 38 , as well as by binding to its extracellular ligands and receptors upon secretion 5,6,14,24,30,33,37,[39][40][41][42][43][44][45][46][47][48] .…”

Section: Introductionmentioning

confidence: 99%

Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

Rahman

Muppala

et al. 2020

Cell Death Dis

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Thrombospondin-4 (TSP-4) attracted renewed attention recently as a result of assignment of new functions to this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP-4 promotes local vascular inflammation in a mouse atherosclerosis model. A common variant of TSP-4, P387-TSP-4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP-4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages in more detail. We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture and in vivo in the model of LPS-induced peritonitis. In tissues and in cell culture, TSP-4 expression was associated with inflammation: TSP-4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFγ, GM-CSF, and LPS, induced TSP-4 expression in macrophages in vivo and in cell culture. Deficiency in TSP-4 in macrophages from Thbs4 −/− mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into a pro-inflammatory phenotype. Expression of TSP-4, especially more active P387-TSP-4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP-4 and reduced migration in presence of TSP-4, and these responses were further increased with P387 variant. We concluded that TSP-4 expression in macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP-4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP-4 was found to be the more active form of TSP-4 in all examined functions.

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“…Even though we did not detect changes in RNA expression, we observed an intracellular staining of TSP-4 in cartilage tissues of all three OA severity grades, pointing to an intracellular function in addition to its structural role. Intracellularly, TSP-4 was shown to be involved in the endoplasmic reticulum (ER) stress response [55], acting as a chaperone in protein folding and trafficking as well as secretion [55,56]. More related to the ECM, it was shown that TSP-1 is involved in Col I processing and assembly [57].…”

Section: Discussionmentioning

confidence: 99%

The Expression of Thrombospondin-4 Correlates with Disease Severity in Osteoarthritic Knee Cartilage

Maly

Schaible

Riegger

et al. 2019

IJMS

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Osteoarthritis (OA) is a progressive joint disease characterized by a continuous degradation of the cartilage extracellular matrix (ECM). The expression of the extracellular glycoprotein thrombospondin-4 (TSP-4) is known to be increased in injured tissues and involved in matrix remodeling, but its role in articular cartilage and, in particular, in OA remains elusive. In the present study, we analyzed the expression and localization of TSP-4 in healthy and OA knee cartilage by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot. We found that TSP-4 protein expression is increased in OA and that expression levels correlate with OA severity. TSP-4 was not regulated at the transcriptional level but we detected changes in the anchorage of TSP-4 in the altered ECM using sequential protein extraction. We were also able to detect pentameric and fragmented TSP-4 in the serum of both healthy controls and OA patients. Here, the total protein amount was not significantly different but we identified specific degradation products that were more abundant in sera of OA patients. Future studies will reveal if these fragments have the potential to serve as OA-specific biomarkers.

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Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Cited by 24 publications

References 55 publications

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

The Expression of Thrombospondin-4 Correlates with Disease Severity in Osteoarthritic Knee Cartilage

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