Granzymes in cardiovascular injury and disease

Zeglinski, Matthew R.; Granville, David J.

doi:10.1016/j.cellsig.2020.109804

Cited by 37 publications

(24 citation statements)

References 148 publications

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“…S1b, supplementary material 3c). These granzyme molecules have been previously implicated in impaired wound healing development by promoting chronic inflammation, vascular dysfunction, and reduced cell adhesion [34]. We also observed a unique CD4 + cluster (cluster 10, Fig.…”

Section: Resultsmentioning

confidence: 53%

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

Theocharidis

Thomas

Sarkar

et al. 2021

Preprint

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To understand the diabetic wound healing microenvironment, we profiled 174,962 single cells from foot, forearm, and PBMCs using single-cell RNA sequencing (scRNASeq) approach. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 genes and M1 macrophage polarization in the DFU patients with healing wounds. Further, scRNASeq of spatially separated samples from same patient and spatial transcriptomics (ST) revealed preferential localization of these healing associated fibroblasts toward deep wound/ulcer bed as compared to wound edge or non-wounded skin. ST also validated our findings of higher enrichment of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.

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Section: Resultsmentioning

confidence: 53%

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

Theocharidis

Thomas

Sarkar

et al. 2021

Preprint

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“…The gene encodes a member of the granzyme subfamily of proteins, which is secreted by natural killer cells and cytotoxic T lymphocytes. The protein has been implicated in coronary artery disease and cardiac fibrosis (53). Interestingly, in a recent study investigating CD8 + T cells in mice under obese/ non-obese NASH, gene expression of GZMB and IL-10 was significantly higher in the obese NASH model, suggesting a common pathway of regulation (54).…”

Section: Discussionmentioning

confidence: 96%

Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

Kanoni

Kumar²,

Amerikanou

et al. 2021

Front. Immunol.

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Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m2) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m2) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene (LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene (MPC1) and the sphingolipid transporter-1 gene (SPNS1) associated with hemoglobin levels, the transforming growth factor‐beta‐induced gene (TGFBI) and the micro-RNA 129-1 (MIR129-1) associated with IL-6 and the granzyme B gene (GZMB) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03135873.

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“…Further study is required to elucidate the molecular mechanisms by which GrK triggers sVEGFR1 release from endothelial cells. It is becoming more recognized that granzymes not solely trigger cell death in target cells, but that they also can exert multiple other functions both inside cells and in the extracellular milieu (17,30). Once in the extracellular matrix, granzymes can contribute to inflammation, vascular dysfunction, vascular permeability, reduced cell adhesion, release of matrix-bound growth factors, extracellular matrix remodeling, re-epithelialization, and remodeling during wound healing (30).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of extracellular granzymes, however, remains poorly understood. Several studies have demonstrated physiological relevance of noncytotoxic functions of extracellular GrB, including tissue remodeling and angiogenesis (30)(31)(32). Extracellular GrB cleaves fibronectin, resulting in a reduction of endothelial cell adhesion to fibronectin as well as reduced endothelial cell migration and tubule formation (33).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Granzyme K Modulates Angiogenesis by Regulating Soluble VEGFR1 Release From Endothelial Cells

Dijk

Meeldijk

et al. 2021

Front. Oncol.

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Angiogenesis is crucial for normal development and homeostasis, but also plays a role in many diseases including cardiovascular diseases, autoimmune diseases, and cancer. Granzymes are serine proteases stored in the granules of cytotoxic cells, and have predominantly been studied for their pro-apoptotic role upon delivery in target cells. A growing body of evidence is emerging that granzymes also display extracellular functions, which largely remain unknown. In the present study, we show that extracellular granzyme K (GrK) inhibits angiogenesis and triggers endothelial cells to release soluble VEGFR1 (sVEGFR1), a decoy receptor that inhibits angiogenesis by sequestering VEGF-A. GrK does not cleave off membrane-bound VEGFR1 from the cell surface, does not release potential sVEGFR1 storage pools from endothelial cells, and does not trigger sVEGFR1 release via protease activating receptor-1 (PAR-1) activation. GrK induces de novo sVEGFR1 mRNA and protein expression and subsequent release of sVEGFR1 from endothelial cells. GrK protein is detectable in human colorectal tumor tissue and its levels positively correlate with sVEGFR1 protein levels and negatively correlate with T4 intratumoral angiogenesis and tumor size. In conclusion, extracellular GrK can inhibit angiogenesis via secretion of sVEGFR1 from endothelial cells, thereby sequestering VEGF-A and impairing VEGFR signaling. Our observation that GrK positively correlates with sVEGFR1 and negatively correlates with angiogenesis in colorectal cancer, suggest that the GrK-sVEGFR1-angiogenesis axis may be a valid target for development of novel anti-angiogenic therapies in cancer.

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Granzymes in cardiovascular injury and disease

Cited by 37 publications

References 148 publications

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

Extracellular Granzyme K Modulates Angiogenesis by Regulating Soluble VEGFR1 Release From Endothelial Cells

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