Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling

Zhao, Rongrong; Ackers‐Johnson, Matthew; Stenzig, Justus; Chen, Chen; Ding, Tao; Zhou, Yue; Wang, Peipei; Ng, Shi Ling; Li, Peter Y.; Teo, Gavin; Rudd, Pauline M.; Fawcett, James W.; Foo, Roger

doi:10.1161/circulationaha.117.030353

Cited by 49 publications

(47 citation statements)

References 67 publications

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“…Overexpression of ARSB was able to reverse the inhibitory effect of DHT on DKK3 expression in PEC (Figure G). Multiple studies have shown the impact of DKK3 inhibition on Wnt signaling, with subsequent impact on proliferation and remodeling pathways …”

Section: Discussionmentioning

confidence: 99%

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Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

2019

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Background:In tissue microarrays, immunostaining of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) was less in recurrent prostate cancers and in cancers with higher Gleason scores. In cultured prostate stem cells, decline in ARSB increased Wnt signaling through effects on Dickkopf Wnt Signaling Pathway Inhibitor (DKK)3. The effects of androgen exposure on ARSB and the impact of decline in ARSB on Wnt signaling in prostate tissue were unknown.Methods: Epithelial and stromal tissues from malignant and normal human prostate were obtained by laser capture microdissection. mRNA expression of ARSB, galactose-6-sulfate-sulfatase (GALNS) and Wnt-signaling targets was determined by QPCR.Non-malignant human epithelial and stromal prostate cells were grown in tissue culture, including two-cell layer cultures. ARSB was silenced by specific siRNA, and epithelial cells were treated with stromal spent media following treatment with IWP-2, an inhibitor of Wnt secretion, and by exogenous recombinant human Wnt3A.Promoter methylation was detected using specific DKK3 and ARSB promoter primers.The effects of DHT and of ARSB overexpression on DKK expression were determined. Cell proliferation was assessed by BrdU incorporation.Results: Normal stroma showed higher expression of vimentin, ARSB, and Wnt3A than epithelium. Normal epithelium had higher expression of E-cadherin, galactose 6sulfate-sulfatase (GALNS), and DKK3 than stroma. In malignant epithelium, expression of ARSB and DKK3 declined, and expression of GALNS and Wnt signaling targets increased. In cultured prostate epithelial cells, Wnt-mediated signaling was greatest when ARSB was silenced and cells were exposed to exogenous Wnt3A. Exposure to 5α-dihydrotestosterone (DHT) increased ARSB and DKK3 promoter rmethylation, and effects of DHT on DKK3 expression were reversed when ARSB was overexpressed. Conclusions: Androgen-induced declines in ARSB and DKK3 may contribute to prostate carcinogenesis by sustained activation of Wnt signaling in prostate epithelium in response to stromal Wnt3A. K E Y W O R D S arylsulfatase B, DHT, DKK3, methylation, Wnt3A 2 | BHATTACHARYYA ET AL. 690 1 | INTRODUCTION Chondroitin sulfates are present in significant amounts throughout mammalian tissues, including epithelium and stroma in all organs. With other glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, and hyaluronan, and by interactions with collagen, protein components of proteoglycans, and structural proteins, they form the framework that is necessary for proper tissue structure and function. The chondroitin sulfatase arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes 4-sulfates from the non-reducing end of chondroitin 4-sulfate (C4S) and is required for the subsequent degradation of C4S by glycosidases. 1-3 The chondroitin sulfatase galactose 6-sulfate-sulfatase (GALNS; N-acetylgalactosamine-6-sulfatase) removes 6-sulfate groups from chondroitin 6-sulfate (C6S) or chondroitin 4,6-disulfate (chondroitin sulfate E),...

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Section: Discussionmentioning

confidence: 99%

“…Increases in chondroitin sulfate and the chondroitin sulfate proteoglycan versican were identified in more aggressive prostate cancers . Increased C4S has significant consequences for transcription, signaling, metabolism, and proliferation in the prostate and in other tissues …”

Section: Introductionmentioning

confidence: 99%

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

2019

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“…In areas more distant from the surface of the cells, chondroitin-and dermatan sulfate-containing proteoglycans (CSPGs and DSPGs respectively) predominate 151 . In both human patients with heart failure and in animal models of myocardial disease, CSPGs accumulate in fibrotic regions 152 . The ECM in the pressure-overloaded heart is also enriched with a wide range of small leucine rich proteoglycans (SLRPs), such as biglycan, decorin, fibromodulin, lumican and osteoglycin.…”

Section: Matricellular Proteinsmentioning

confidence: 99%

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Frangogiannis

2019

Circulation Research

371

287

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The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

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“…The preceding descriptions regarding inflammation and therapeutic pathways using GAGs are equally applicable to CAD, also known as coronary heart disease, and to other cardiovascular diseases. Studies have found that countering the degradation of GAGs, in particular the accumulation of CS/DS in myocardial cells, is a major therapeutic pathway for several cardiovascular diseases [ 48 , 123 , 124 ].…”

Section: Xylose/xylitol Hypertension Acute Kidney Injury Coronary mentioning

confidence: 99%

Correlation of D-xylose with severity and morbidity-related factors of COVID-19 and possible therapeutic use of D-xylose and antibiotics for COVID-19

Cheudjeu¹

2020

Life Sciences

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The SARS-Cov-2 pandemic that currently affects the entire world has been shown to be especially dangerous in the elderly (≥65 years) and in smokers, with notably strong comorbidity in patients already suffering from chronic diseases, such as Type 2 diabetes, cancers, chronic respiratory diseases, obesity, and hypertension. Inflammation of the lungs is the main factor leading to respiratory distress in patients with chronic respiratory disease and in patients with severe COVID-19. Several studies have shown that inflammation of the lungs in general and Type 2 diabetes are accompanied by the degradation of glycosaminoglycans (GAGs), especially heparan sulfate (HS). Several studies have also shown the importance of countering the degradation of HS in lung infections and Type 2 diabetes. D-xylose, which is the initiating element for different sulfate GAG chains (especially HS), has shown regeneration properties for GAGs. D-xylose and xylitol have demonstrated anti-inflammatory, antiglycemic, antiviral, and antibacterial properties in lung infections, alone or in combination with antibiotics. Considering the existing research on COVID-19 and related to D-xylose/xylitol, this review offers a perspective on why the association between D-xylose and antibiotics may contribute to significantly reducing the duration of treatment of COVID-19 patients and why some anti-inflammatory drugs may increase the severity of COVID-19. A strong correlation with scurvy, based on gender, age, ethnicity, smoking status, and obesity status, is also reviewed. Related to this, the effects of treatment with plants such as Artemisia are also addressed. Chemical compounds D-xylose; xylitol; l -ascorbic Acid; D-glucuronic acid; N -acetylglucosamine; D- N -acetylglucosamine; N -acetylgalactosamine; galactose.

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Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling

Abstract: CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.

Cited by 49 publications

References 67 publications

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Correlation of D-xylose with severity and morbidity-related factors of COVID-19 and possible therapeutic use of D-xylose and antibiotics for COVID-19

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