Table 1.
Alterations or roles of GAGs/PGs in different diseases.
| Pathology Types | Study Objects (Cells/Tissues) | GAGs/PGs Alterations | References |
|---|---|---|---|
| Atherosclerotic type II | Aorta | Both the total CS content and the ratio of 6-O-S/4-O-S disaccharides in type II atherosclerosis arteries were increased | [50] |
| Atherosclerosis | Arterial smooth muscle cells | TGF-β prolongs CS chains in arterial smooth muscle cells and increases versican binding to LDL. | [51] |
| Atherosclerosis (symptomatic carotid stenosis) | Iliac arteries | The expression of perlecan gene decreased while versican gene remained unchanged. | [53] |
| Atherosclerosis and vascularrestenosis | Macrophages | Syndecan-1 protein level in macrophages was significantly decreased under hypoxia condition, and mRNA expression of key enzymes involved in HS biosynthesis in hypoxia cells was decreased. In addition, hypoxia also reduced the relative content of HS. | [58] |
| Atherosclerosis and vascularrestenosis | Aortic smooth muscle cells | HA and HA synthase are increased in senescent cells. HA accumulation promotes SMC metastasis via ERK1/2 modulation of the CD44 signaling pathway, resulting in intimal hyperplasia. | [61] |
| Atherosclerosis | Macrophages | LMW-HA induces macrophage/foam cell production and promotes atherosclerosis via the PKC pathway. LMW-HA also amplifies the migration of monocytes to inflammatory atherosclerotic plaques. | [65] |
| Breast cancer | Tumor tissue and plasma | Perlecan is absent in epithelial cell basement membrane while markedly upregulated in stroma. Furthermore, plasma perlecan level was significantly higher in estrogen receptor (ER)+ patients than ER- patients. | [78] |
| Prostate cancer | Perlecan expression is increased, which can the regulate sonic hedgehog signaling path. | [79] | |
| Neuroendocrine tumors (NETs) | Tumor tissue | Syndecan-2 is significantly increased in well-differentiated NETs and significantly decreased in poorly differentiated NETs. Glypican-5 was overexpressed in high-grade tumors with epithelial differentiation, but not in tumors with neuroendocrine phenotype. | [80] |
| Breast cancer | Tumor tissue | The GAG length increased by approximately 15% in tumor tissue compared to normal tissue. Both the 6-O-S CS and the total sulfation of HS increased. Compared to nonfatal breast cancers, the sulfation degree of HS, particularly 6-O-S, was decreased in fatal breast cancers, whereas the proportion of non-sulfated disaccharides was increased. | [87] |
| Glioblastoma multiforme (GBM) | Tumor tissue | 60–65% of GBM tumor samples showed increased levels of CS. A 1.5-fold increase in decorin, a 3-fold increase in biglycan and a 2-fold increase in serglycin. Only decorin levels were negatively associated with overall survival in GBM patients. | [115] |
| Pancreatic carcinoma | Tumor tissue | The total GAG level was increased by 4 times, HA increased 12 times, CS increased 22 times, DS increased 1.5 times. A significant increase in non-sulfate and 6-sulfate disaccharides of CS. | [127] |
| Pancreatic carcinoma | Tumor tissue | There are 27-fold and 7-fold increases in versican and decorin, respectively, compared with normal pancreases. The expression of 6-O-S and non-sulfated disaccharide units are enhanced. | [130] |
| Prostate cancer | Tumor tissue | Prostate cancer has an elevated 4-O-S CS content in the ECM, which may be due to inhibited androgen receptor (AR) signaling, thus resulting in increased 4-O-sulfotransferase CHST11 expression. | [131] |
| Gastric cancer | Tumor tissue | CS has a 10-fold increase in 6-O-S and non-disaccharide units, while 4-O-S disaccharides were correspondingly decreased. | [132] |
| Ovarian adenocarcinoma | Tumor tissue | High expression of CS-E in the ECM of ovarian adenocarcinoma enhances vascular endothelial growth factor (VEGF) mediation. | [133] |
| Lung cancer | Lewis lung carcinoma cells | The proportion of Δ4.5HexA-GalNAc-4, 6-O-disulfate was higher in highly metastatic lung cancer cell lines than in low metastatic cell lines. | [134] |
| Breast cancer | Tumor tissue | HA was significantly increased in 143 tumor tissue samples, indicating that HA is directly involved in breast cancer metastasis. | [143] |
| Breast cancer | Breast tumor cells (MDA-MB-231 cells) | LMW-HA activates actin filament-associated protein (AFAP-110) to bind to F-actin, resulting in nuclear translocation of myeloiddifferentiation factor (MyD88)/NF-xB and enhanced expression of pro-inflammatory cytokines IL-1β and IL-8. AFAP-110 binding with F-actin also promoted tumor cell metastasis. | [149] |
| Diabetes mellitus 1 type (T1D) | Pancreas | HSPGs such as Col18 and syndecan-1 showed significant loss in T1D human islets. | [162] |
| Diabetes mellitus | GAG (including perlecan) sulfation patterns affected amyloid fibril formation. The order of impact was heparin > N-desulfated acetylated heparin > fully desulfated N-sulfated heparin > fully desulfated N-acetylated heparin. | [175] | |
| Diabetic nephropathy | Glomerulus | Heparin sulfate 6-O-S plays an important role in extracellular matrix remodeling. Regulation of VEGFA and FGF2 signaling was achieved by increasing the expression of 6-O-endosulfatases Sulf1 and Sulf2 by the transcription factor Wilms’ Tumor 1 (WT1). | [183] |
| Diabetic nephropathy | Kidneys of rats | HS has less N-S in the GBM of diabetic rats compared to the normal group. | [184] |
| Diabetic nephropathy | Kidneys of rats | Renal CS/DS content decreased, accompanied by a decrease in the degree of sulfation, particularly 4, 6-O-sulfated GalN content. | [187] |
| Diabetic nephropathy | Renal cortex of diabetic db/db mice | 4-O-disaccharide sulfate significantly decreased from 65% to 40%, whereas 6-O-S disaccharide decreased from 11% to 6% and non-sulfated disaccharide increased from 21.5% to 51% in the renal cortex of diabetic db/db mice. | [186] |
| T2D | Urine | The contents of total GAGs, CS/DS, and HS in urine were significantly higher than those in healthy subjects. | [188] |
| Diabetes mellitus | Urine | 6-O-S and the 6-O-S/4-O-S ratio in the urine of diabetic patients with microalbuminuria were significantly increased compared with the healthy group. | [189] |
| Alzheimer’s disease (AD) | Brain | 4-O-S and 6-O-S CS are found in neurofibrillary tangles (NFTs) of AD patients, while only 4-O-S CS is found in senile plaques (SPs). | [207] |
| Multiple sclerosis | White matter | CSPGs (versican, neurocan, and aggrecan) and DSPGs were mainly located at the edge of active plaques, while the content of CSPGs in the active center of MS plaques was significantly decreased, possibly due to the internalization of PGs in PNNs by their foam macrophages together with myelin. | [208] |
| AD | Brain | PGs were more abundant in areas with amyloid plaques and neurofibrillary tangles. For example, relative to healthy individuals, the total PGs increased 1.6-fold in the AD hippocampus and 3.4-fold in the superior frontal gyrus (superior gyrus frontalis). Among them, HSPGs increased the most. | [217] |
| AD | Occipital neocortical and hippocampal tissue | Fibrillar Aβ plaques and nonfibrillar Aβ plaques contained high levels of N-sulfated HS, while N-sulfation was very low in nonfibrillar Aβ plaques. | [218] |
| AD | Cerebral cortex | The critical sites for binding of heparin sulfate to β-amyloid (Aβ) fibrils contain 2-O-S IdoA and N-S from the human cerebral cortex, whereas binding of Aβ monomers requires 6-O-S on GlcN residues. | [219] |
| Parkinson’s disease (PD) | Neuronal cells | The internalization of α-syn aggregates strongly depends on the cell surface HS and is associated with their total sulfation level. | [224] |
| COVID-19 infection | N-S, 2-O-S, and 6-O-S in HS and 6-O-S, 2-O-S, 3-O-S, and N-S in HP were critical for competitive binding to SARS-CoV-2 spike protein. | [241] | |
| COVID-19 infection | The presence of 3-O-S in HS contributes to the recognition and binding of SARS-CoV-2 spikes in vitro. | [242] | |
| COVID-19 infection | 3-O-sulfotransferase 3B overexpression and glycocalyx sulfation degree were too low to promote SARS-CoV-2 infection under pathological conditions. | [243] | |
| Idiopathic pulmonary fibrosis | Lung | CS/DS, HA, and the CS/DS ratio increased significantly. CS/DS increases in 4-O-S, 6-O-S, and 2-O-S disaccharide units and decreases in non-sulfated disaccharides, resulting in significant increases in sulfated levels. Similarly, significant increases were observed in NS, 2-O-S, and 6-O-S disaccharides of HS, particularly the UA2S–GlcNS6S unit. | [247] |
| Asthma | Endobronchial biopsy specimens | Significant increases in PG (versican, biglycan, and decorin) content at the lesion were observed in biopsy specimens from asthma cases. | [248] |
| Chronic obstructive pulmonary disease | Lung | HS increased significantly, and its sulfation pattern was related to the COPD stage, while CS/DS did not change significantly. The 2-O-S and NS of HS increased during the fourth phase of COPD, while 6-O-S did not change. | [249] |
| Cystic fibrosis | Lung | GAG expression is elevated in cystic fibrosis and abnormal sulfation of GAG can be found in bronchial epithelial cells of patients. | [250,251] |
| Familial urolithiasis | Urine | The total sulfated GAG, CS, and HS contents in urine all decreased, while the HA content was increased, and the proportion of HS in total sulfated GAGs was increased. | [259] |
| Kidney stones | Urine | Black South Africans were found to have higher CS levels in urine than whites (kidney stones were significantly more prevalent in whites than blacks in South Africans), suggesting that higher CS levels may inhibit kidney stone formation. | [260] |