New mechanistic insights to PLOD1-mediated human vascular disease

Koenig, Sara N.; Cavus, Omer; Williams, Jeremy C.; Bernier, Matthew C.; Tonniges, Jeff; Sucharski, Holly C.; Dew, Trevor; Akel, Muhannad; Baker, Peter B.; Madiai, Francesca; Giorgi, Francesca De; Scietti, Luigi; Faravelli, Silvia; Forneris, Federico; Mohler, Peter J.; Bradley, Elisa A.

doi:10.1016/j.trsl.2021.08.002

Cited by 10 publications

(13 citation statements)

References 50 publications

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“…Pathogenic variants in PLOD1 are associated with the kyphoscoliotic type of EDS typically characterized by hyperextensible skin and joint tissue ( 73 , 74 ). Several studies have identified inactivating PLOD1 variants in families with TAA and dissection ( 75 , 76 ). Similarly, prolyl hydroxylase enzymes, including P3H1 and P4HA2, catalyzing the hydroxylation of proline residues are critical for collagen triple helix formation and fiber stability.…”

Section: Discussionmentioning

confidence: 99%

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects

Yang,

Feng,

Tang

et al. 2024

Sci. Transl. Med.

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Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)–associated pathogenic variant ( TGFBR1 A230T ). We also generated hiPSC-derived BVGs using cells from a patient with LDS ( Patient A230T/+ ) and using genetically corrected cells ( Patient +/+ ). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1 A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in Patient A230T/+ BVGs compared with Patient +/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in Patient A230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in Patient A230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.

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Section: Discussionmentioning

confidence: 99%

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects

Yang,

Feng,

Tang

et al. 2024

Sci. Transl. Med.

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“…PLODs encode the lysyl hydroxylase (LH) protein, which is involved in the biosynthesis of collagen. Therefore, abnormal or altered expression of PLODs could be a potential factor in the pathogenesis of some diseases [ 31 , 32 ]. This could be the result of various factors including the induction of epithelial–mesenchymal transition (EMT) in response to PLOD overexpression.…”

Section: Discussionmentioning

confidence: 99%

PLODs: Novel prognostic biomarkers and potential immunotherapy targets for head and neck squamous cell carcinoma

Gong¹,

Wu²,

Duan³

et al. 2023

Heliyon

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“…Vascular homeostasis imbalance was also identified as a factor in atherosclerosis progression. It has been reported that dysfunction of endothelium and VSMCs, an early marker of atherosclerosis, can disrupt the balance between vasoconstriction and vasodilation, thereby promoting the inflammatory response and exacerbating atherosclerosis ( Nkoenig et al, 2022 ; Alberts et al, 2002 ; Davignon and Ganz, 2004 ). The top inflammation marker (HSPA6) and the top network markers according to a degree (PXN and MAP3K3) in our results indicated an effect of endothelial cells and VSMCs.…”

Section: Discussionmentioning

confidence: 99%

“…PLOD1 encodes lysyl hydroxylase-1, which is essential for ECM maturation. ECM proteolytic fragments affect a variety of functions and properties of inflammatory and immune cells ( Adairkirk and Senior, 2008 ); ECM was also relevant to the integrity and stability of VSMCs ( Nkoenig et al, 2022 ). It has been reported that inflamm-aging can lead to changes in vascular structure and aging of VSMCs ( Chi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

Chen

Yao

et al. 2022

Front. Genet.

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Background: Atherosclerosis, one of the main threats to human life and health, is driven by abnormal inflammation (i.e., chronic inflammation or oxidative stress) during accelerated aging. Many studies have shown that inflamm-aging exerts a significant impact on the occurrence of atherosclerosis, particularly by inducing an immune homeostasis imbalance. However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models.Methods: First, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis.Results: Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging.Conclusion: In summary, we developed a model integrating crucial risk factors in inflamm-aging and atherosclerosis. Our computation pipeline could be used to explore potential mechanisms of related diseases.

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New mechanistic insights to PLOD1-mediated human vascular disease

Cited by 10 publications

References 50 publications

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects

PLODs: Novel prognostic biomarkers and potential immunotherapy targets for head and neck squamous cell carcinoma

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

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