Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification

Seime, Till; Akbulut, Asim Cengiz; Liljeqvist, Moritz Lindquist; Siika, Antti; Jin, Hong; Winski, Greg; Gorp, Rick H. van; Karlöf, Eva; Lengquist, Mariette; Buckler, Andrew J.; Kronqvist, Malin; Waring, Olivia J.; Lindeman, J.; Biessen, Erik A. L.; Maegdefessel, Lars; Razuvaev, Anton; Schurgers, Leon J.; Hedin, Ulf; Matic, Ljubica

doi:10.3390/cells10061276

Cited by 14 publications

(10 citation statements)

References 68 publications

(105 reference statements)

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“…This upregulation of SMC markers also correlated with increased expression of recently characterized SMC calcification markers (e.g. proteoglycan 4 ( PRG4 ) 66 . This is further supported by gene ontology enrichment analysis highlighting calcium signaling, cytoskeletal rearrangements, and muscle contraction as overrepresented pathways among differentially expressed genes between highly and lowly calcified lesions 65 .…”

Section: Discussionsupporting

confidence: 54%

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

Wong

Auguste

Cardenas

et al. 2022

Preprint

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Background: Genome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and hypertension. However, the lack of mechanistic insights for a majority of these loci limits translation of these findings into the clinic. Among these loci with unknown functions is UFL1-FHL5 (chr6q16.1), a locus that reached genome-wide significance in a recent CAD/MI GWAS meta-analysis. In addition to CAD/MI, UFL1-FHL5 is also implicated to coronary calcium, intracranial aneurysm, and migraine risk, consistent with the widespread pleiotropy observed among other GWAS loci. Methods: We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and imaging of human coronary artery tissues to implicate Four-and-a-half LIM domain 5 (FHL5) as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments. Results: We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through eQTL colocalization methods. FHL5 gene expression was enriched in the SMC and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating SMC contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream CAD/MI loci, such as FOXL1 and FN1 that have roles in vascular remodeling. Conclusion: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling loci. These trans-acting mechanisms may account for a portion of the heritable risk for complex vascular diseases.

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Section: Discussionsupporting

confidence: 54%

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

Wong

Auguste

Cardenas

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This upregulation of SMC markers also correlated with increased expression of recently characterized SMC calcification markers (eg, proteoglycan 4 ( PRG4 ). 72 This is further supported by gene ontology enrichment analysis highlighting calcium signaling, cytoskeletal rearrangements, and muscle contraction as overrepresented pathways among differentially expressed genes between highly and lowly calcified lesions. 71 To reconcile these phenotypes, we speculate that FHL5 regulation of intracellular calcium ion homeostasis contributes to both processes, given the critical role of calcium in the initiation of SMC contraction, 73,74 cell stiffness, 75,76 and vascular calcification.…”

Section: Discussionmentioning

confidence: 76%

FHL5 Controls Vascular Disease–Associated Gene Programs in Smooth Muscle Cells

Wong

Auguste

Cardenas

et al. 2023

Circulation Research

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Background: Genome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is UFL1 –four-and-a-half LIM domain 5 ( FHL5 ; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. UFL1-FHL5 is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci. Methods: We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate FHL5 as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells. Results: We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through expression quantitative trait locus colocalization methods. FHL5 gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease/myocardial infarction loci, such as FOXL1 and FN1 that have roles in vascular remodeling. Conclusions: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases.

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“…Our data also suggest that lubricin in plasma is altered by age and in metabolic syndrome manifested as increased BMI. Lubricin has been indicated to be involved in both atherosclerosis 45 and in high-fat-diet induced glycose intolerance 46 . Changed glycosylation of lubricin in these diseases are likely to contribute to the disease progress.…”

Section: Discussionmentioning

confidence: 99%

A Novel Fluorescent Immuno-Lectin Assay to Identify Osteoarthritis Associated Glycoforms of Lubricin

Afshari,

Thomsson,

Höglund

et al. 2024

Preprint

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Lubricin or proteoglycan-4 (PRG-4) is a mucinous glycoprotein lubricating the cartilage and maintaining normal tissue function and cell-homeostasis. AlteredO-glycoforms of lubricin has been found in osteoarthritis (OA) synovial fluid (SF). Here, we utilized a Fluorescent Immuno-Lectin Assay (FILA) to measure the levels of lubricin glycoforms in plasma/SF and their potential as biomarkers for disease. Five different lectins were used in the assay: Macrophage Galactose-type lectin (MGL),Sambucus NigraAgglutinin (SNA),Maackia AmurensisAgglutinin (MAA), Peanut Agglutinin (PNA), and Galectin-3 (Gal-3). Our results showed that the levels of lubricin glycoforms in late-stage knee OA plasma (typically <10 μg/ml) are 1-3 order of magnitude lower than in OA SF (typically> 100 μg/ml). Furthermore, plasma lubricin glycans displayed higher level of sialylation, while SF derived lubricin displayed higher level of Tn-antigens. In OA patients we found decreased level in plasma of SNA binding lubricin (p=0.0023) compared to controls. This lectin binds 6 linked sialic acid. In addition, we found that lubricin glycoforms correlated both with Body Mass Index (BMI) and age, especially in regards of sialylation as measured by both MAA and SNA. Our data suggest that glycosylation of lubricin is different comparing SF with plasma. Moreover, the glycosylation of plasma lubricin is altered in OA patients compared controls.

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Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification

Cited by 14 publications

References 68 publications

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

FHL5 Controls Vascular Disease–Associated Gene Programs in Smooth Muscle Cells

A Novel Fluorescent Immuno-Lectin Assay to Identify Osteoarthritis Associated Glycoforms of Lubricin

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