Understanding the evolving phenotype of vascular complications in telomere biology disorders

Higgs, Cecilia; Crow, Yanick J.; Adams, Denise M.; Chang, Emmanuel; Hayes, Don; Herbig, Utz; Huang, James N.; Himes, Ryan; Jajoo, Kunal; Johnson, F. Brad; Reynolds, Susan D.; Yonekawa, Yoshihiro; Armanios, Mary; Boulad, Farid; DiNardo, Courtney D.; Dufour, Carlo; Goldman, Frederick D.; Khan, Shakila P.; Kratz, Christian P.; Myers, Kasiani C.; Raghu, Ganesh; Alter, Blanche P.; Aubert, Geraldine; Bhala, Sonia; Cowen, Edward W.; Dror, Yigal; El–Youssef, Mounif; Friedman, Bruce; Giri, Neelam; Guba, Lisa Helms; Khincha, Payal P.; Lin, Tiffany; Longhurst, Hilary; McReynolds, Lisa J.; Nelson, Adam; Olson, Tim; Pariser, Anne; Perona, Rosario; Sasa, Ghadir; Schratz, Kristen E.; Simonetto, Douglas A.; Townsley, Danielle M.; Walsh, Michael F.; Stevens, Kate; Agarwal, Suneet; Bertuch, Alison A.; Savage, Sharon A.

doi:10.1007/s10456-018-9640-7

Cited by 40 publications

(27 citation statements)

References 41 publications

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“…Moreover, gene analysis was applied to detect the alteration of mitochondrial mitosis‐related factors. In Figure c–e, the transcription of Drp1 and Mff were largely augmented by hyperglycemia stress, indicative of the activation of mitochondrial mitosis‐related factors (Hernandez et al, ; Higgs et al, ). However, Mst1 knockdown could inhibit the hyperglycemia‐induced upregulation of Drp1 and Mff (Figure c–e), reconfirming that Mst1 positively regulates mitochondrial mitosis.…”

Section: Resultsmentioning

confidence: 94%

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Qin

Lin

Zhang

et al. 2019

Journal Cellular Physiology

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Diabetes is a leading cause of microvascular complications, such as nephropathy and retinopathy. Recent studies have proposed that hyperglycemia-induced endothelial cell dysfunction is modulated by mitochondrial stress. Therefore, our experiment was to detect the upstream mediator of mitochondrial stress in hyperglycemia-treated endothelial cells with a focus on macrophage-stimulating 1 (Mst1) and mitochondrial fission. Our data illuminated that hyperglycemia incubation reduced cell viability, as well as increased apoptosis ratio in endothelial cell, and this alteration seemed to be associated with Mst1 upregulation. Inhibition of Mst1 via transfection of Mst1 siRNA into an endothelial cell could sustain cell viability and maintain mitochondrial function. At the molecular levels, endothelial cell death was accompanied with the activation of mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial fission. Genetic ablation of Mst1 could reduce mitochondrial oxidative injury, block mitochondrial apoptosis, and repress mitochondrial fission. Besides, we also found Mst1 triggered mitochondrial dysfunction as well as endothelial cell damage through augmenting JNK pathway. Suppression of JNK largely ameliorated the protective actions of Mst1 silencing on hyperglycemia-treated endothelial cells and sustain mitochondrial function. The present study identifies Mst1 as a primary key mediator for hyperglycemia-induced mitochondrial damage and endothelial cell dysfunction. Increased Mst1 impairs mitochondrial function and activates endothelial cell death via opening mitochondrial death pathway through JNK. K E Y W O R D S endothelial cells, hyperglycemia, JNK pathway, mitochondria, Mst1

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Section: Resultsmentioning

confidence: 94%

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Qin

Lin

Zhang

et al. 2019

Journal Cellular Physiology

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“…Although there are limited data about neuropathic complications in patients with shortened TL undergoing chemotherapy, it is possible that impaired regenerative potential of peripheral nerves caused her severe neuropathy. Similarly, there are emerging data on vascular abnormalities in patients with TBDs, which may relate to our patient's capillary leak syndrome. Her syncopal episodes post‐bleomycin were most likely unrelated to her shortened TL and telomerase deficiency.…”

Section: Discussionmentioning

confidence: 84%

Severe therapy‐related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres

Agrusa

Bertuch

DiNardo

et al. 2019

Pediatric Blood & Cancer

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Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17‐year‐old female with Hodgkin lymphoma who developed severe chemotherapy‐related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy‐related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.

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“…Gastrointestinal (GI) bleeding is a relatively common complication of STS and is often secondary to telangiectasias in the small intestine or stomach (gastric antral vascular ectasia). 18 Retinal vascular diseases have also been observed in relation to STS, particularly in patients with DKC, Coats disease, and Revesz syndrome. 18 GI manifestations of STS are less frequently identified, with estimated frequency of up to 16%.…”

Section: Clinical Manifestations Of Short Telomere Syndromesmentioning

confidence: 99%

“…18 Retinal vascular diseases have also been observed in relation to STS, particularly in patients with DKC, Coats disease, and Revesz syndrome. 18 GI manifestations of STS are less frequently identified, with estimated frequency of up to 16%. 19 Reported GI manifestations include enterocolitis, enteropathy, and esophageal strictures.…”

Section: Clinical Manifestations Of Short Telomere Syndromesmentioning

confidence: 99%

Short Telomeres: Cause and Consequence in Liver Disease

Penrice

Simonetto

2020

Semin Liver Dis

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Short telomere syndrome is a genetically inherited syndrome resulting in premature telomere shortening. This premature shortening of telomeres can result in hematologic, pulmonary, vascular, gastrointestinal, and hepatic manifestations of disease. Identifying patients with short telomere syndrome can be a clinical challenge due to the multitude of potential manifestations and lack of widely available diagnostic tests. In this review, we will highlight hepatic manifestations of short telomere syndrome with a focus on diagnosis, testing, and potential treatments.

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Understanding the evolving phenotype of vascular complications in telomere biology disorders

Cited by 40 publications

References 41 publications

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Severe therapy‐related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres

Short Telomeres: Cause and Consequence in Liver Disease

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