The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

Yano, Shoji; Li, C.; Pavlova, Zdena

doi:10.1007/8904_2012_141

Cited by 11 publications

(11 citation statements)

References 15 publications

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“…In a study carried out by Yano et al 22on an autopsy specimen of a deceased MPS I patient, ''phosphorylated Smad2'' immunofluorescent staining revealed a significant signal increase in the vascular wall and the myocardium when compared to the control samples. This supports the increased TGF-β signal (22). In another study investigating the relationship between TGF-β and arterial pathology in MPS I animal models, immunohistochemically investigations of the sclerotic vessels showed TGF-β positivity and an increase in fibronectin (23).…”

Section: Discussionsupporting

confidence: 56%

Evaluation of Cardiovascular Involvement and Cytokine Levels in Patients with Mucopolysaccharidosis

Canda¹,

Köse²,

Kağnıcı³

et al. 2018

jpr

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Cardiovascular involvement is common in patients with mucopolysaccharidoses (MPS). In this study, we investigated the effects of the markers involved in vascular endothelial injury pathogenesis (transforming growth factor β-TGF-β, interleukin-IL 6, IL 10, high sensitive C reactive protein-hs CRP, vascular endothelial growth factor-VEGF, N-terminal pro-Natriuretic peptide-NT-proBNP) and clinical, laboratory and echocardiographic findings of the patients Materials and Methods: A total of 37 patients (5 MPS I, 4 MPS II, 2 MPS IIIa, 4 MPS IIIb, 14 MPS IVa, 8 MPS VI) and 32 controls with similar age and sex were included in the study. Results: Corneal clouding was seen in 29(78%) patients. There were 23 (62%) patients with organomegaly, and 28 (75%) patients with hearing loss. When the groups were compared in terms of NT-proBNP, hsCRP, TGF-β, IL6, IL10 and VEGF levels, there was a statistically significant increase in the patient group for NT-proBNP and VEGF (p = 0.04, p = 0.03, respectively). The carotid intima media thickness was statistically significantly higher in the patient group (p <0.001). Left ventricular diastolic diameter was significantly higher in the patient group (p = 0.009), intraventricular septum thickness was significantly higher in the patient group (p <0.001). E/A ratio was significantly lower in the patient group (p <0.001). Conclusion: Cardiac involvement in MPS patients is a major cause of mortality and morbidity. It is thought that cytokines, proinflammatory markers are elevated in patients with vascular damage like other lysosomal diseases. There is a need for further studies to determine biomarkers for vascular

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Section: Discussionsupporting

confidence: 56%

Evaluation of Cardiovascular Involvement and Cytokine Levels in Patients with Mucopolysaccharidosis

Canda¹,

Köse²,

Kağnıcı³

et al. 2018

jpr

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“…Hyperactive TGF-ß signals in the intimal layer with myointimal proliferation causing stenosis in the coronary arteries as well as in the thickened endocardium and in the myocardial cells have been reported in a patient with MPS-I (Yano et al 2013). Canine models with MPS-I showed consistent findings (Lyons et al 2011).…”

Section: Discussionmentioning

confidence: 82%

Glycosaminoglycan metabolism defects and atherosclerosis: frequent association of endothelial dysfunction in patients with Mucopolysaccharidosis

Yano

Moseley

Wong

et al. 2013

J of Inher Metab Disea

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Cardiovascular lesions, including coronary artery stenosis, are frequently associated and can cause sudden death in patients with genetic defects of glycosaminoglycan (GAG) metabolism. Early diagnosis of coronary artery lesions is difficult, although potentially lifesaving. Histopathological similarities between atherosclerotic changes in adults and in patients with genetic GAG metabolism defects have been known. Atherosclerosis is the result of a complex process involving metabolism of GAGs and proteoglycans preceded by endothelial dysfunction as a key event. Decreased nitric oxide (NO) bioavailability is considered the hallmark of endothelial dysfunction. Reduced NO synthase (NOS) has been reported in atherosclerotic arteries. Impairment in reactive hyperemia-digital peripheral arterial tonometry (RH-PAT) with EndoPAT has been validated to correlate coronary microvascular function in patients with atherosclerosis. RH-PAT is thought to reflect endothelial NO production. Immunohistological staining of endothelial NOS was performed in the stenotic lesions in the coronary artery of a 3-year-old patient with Mucopolysaccharidosis-I, showing decreased activities. This prompted a study to measure endothelial function in patients with GAG metabolism defects for early diagnosis of endothelial dysfunction in the coronary arteries as an early sign of coronary artery changes. Evaluation by RH-PAT in 30 patients with variable genetic defects in GAG metabolism revealed significantly decreased Reactive Hyperemia Indexes compared with 12 controls. Evaluation of endothelial function with RH-PAT in patients with GAG metabolism defects may detect coronary artery lesions that can be underdiagnosed by the other measures such as coronary angiography. Use of this method may prove vital in the management of patients with GAG metabolism defects.

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“…Furthermore, specific targeting of molecular mediators of fibrosis such as TGFβ1 is undergoing clinical trials for FSGS [99]. TGFβ1 is a key fibrogenic cytokine [9-11] and was recently found up regulated the enlarged heart of a patient with mucopolysaccharidosis type I (deficiency of α-L-iduronidase) who died from sudden cardiac failure [100]. The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSD) due to deficiency of enzymes involved in the catabolism of glycosaminoglycans.…”

Section: Beyond Ert: Management Of Fibrosis In Fabry Diseasementioning

confidence: 99%

Fibrosis: a key feature of Fabry disease with potential therapeutic implications

Weidemann

Sánchez-Niño

Politei³

et al. 2013

Orphanet J Rare Dis

136

102

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Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.

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The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

Cited by 11 publications

References 15 publications

Evaluation of Cardiovascular Involvement and Cytokine Levels in Patients with Mucopolysaccharidosis

Evaluation of Cardiovascular Involvement and Cytokine Levels in Patients with Mucopolysaccharidosis

Glycosaminoglycan metabolism defects and atherosclerosis: frequent association of endothelial dysfunction in patients with Mucopolysaccharidosis

Fibrosis: a key feature of Fabry disease with potential therapeutic implications

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