Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease

BACKGROUND: In endothelial cells (ECs), glycolysis, regulated by PFKFB3 (6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase, isoform‐3), is the major metabolic pathway for ATP generation. In preclinical peripheral artery disease models, VEGF(165)a (vascular endothelial growth factor(165)a) and micr...

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Autores principales: Zaied, Abdelrahman A., Ushio‐Fukai, Masuko, Fukai, Tohru, Kovacs‐Kasa, Anita, Alhusban, Suhib, Sudhahar, Varadarajan, Ganta, Vijay C., Annex, Brian H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122893/
https://www.ncbi.nlm.nih.gov/pubmed/36974760
http://dx.doi.org/10.1161/JAHA.122.027986
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author Zaied, Abdelrahman A.
Ushio‐Fukai, Masuko
Fukai, Tohru
Kovacs‐Kasa, Anita
Alhusban, Suhib
Sudhahar, Varadarajan
Ganta, Vijay C.
Annex, Brian H.
author_facet Zaied, Abdelrahman A.
Ushio‐Fukai, Masuko
Fukai, Tohru
Kovacs‐Kasa, Anita
Alhusban, Suhib
Sudhahar, Varadarajan
Ganta, Vijay C.
Annex, Brian H.
author_sort Zaied, Abdelrahman A.
collection PubMed
description BACKGROUND: In endothelial cells (ECs), glycolysis, regulated by PFKFB3 (6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase, isoform‐3), is the major metabolic pathway for ATP generation. In preclinical peripheral artery disease models, VEGF(165)a (vascular endothelial growth factor(165)a) and microRNA‐93 both promote angiogenesis. METHODS AND RESULTS: Mice following hind‐limb ischemia (HLI) and ECs with, and without, hypoxia and serum starvation were examined with, and without, microRNA‐93 and VEGF(165)a. Post‐HLI perfusion recovery was monitored. EC metabolism was studied using seahorse assay, and the expression and activity of major metabolism genes were assessed. Reactive oxygen species levels and EC permeability were evaluated. C57Bl/6J mice generated a robust angiogenic response to HLI, with ECs from ischemic versus nonischemic muscle demonstrating no increase in glycolysis. Balb/CJ mice generated a poor angiogenic response post‐HLI; ischemic versus nonischemic ECs demonstrated significant increase in glycolysis. MicroRNA‐93‐treated Balb/CJ mice post‐HLI showed better perfusion recovery, with ischemic versus nonischemic ECs showing no increase in glycolysis. VEGF(165)a‐treated Balb/CJ mice post‐HLI showed no improvement in perfusion recovery with ischemic versus nonischemic ECs showing significant increase in glycolysis. ECs under hypoxia and serum starvation upregulated PFKFB3. In ECs under hypoxia and serum starvation, VEGF(165)a versus control significantly upregulated PFKFB3 and glycolysis, whereas miR‐93 versus control demonstrated no increase in PFKFB3 or glycolysis. MicroRNA‐93 versus VEGF(165)a upregulated glucose‐6‐phosphate dehydrogenase expression and activity, activating the pentose phosphate pathway. MicroRNA‐93 versus control increased reduced nicotinamide adenine dinucleotide phosphate and virtually eliminated the increase in reactive oxygen species. In ECs under hypoxia and serum starvation, VEGF(165)a significantly increased and miR‐93 decreased EC permeability. CONCLUSIONS: In peripheral artery disease, activation of the pentose phosphate pathway to promote angiogenesis may offer potential therapeutic advantages.
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spelling pubmed-101228932023-04-24 Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease Zaied, Abdelrahman A. Ushio‐Fukai, Masuko Fukai, Tohru Kovacs‐Kasa, Anita Alhusban, Suhib Sudhahar, Varadarajan Ganta, Vijay C. Annex, Brian H. J Am Heart Assoc Original Research BACKGROUND: In endothelial cells (ECs), glycolysis, regulated by PFKFB3 (6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase, isoform‐3), is the major metabolic pathway for ATP generation. In preclinical peripheral artery disease models, VEGF(165)a (vascular endothelial growth factor(165)a) and microRNA‐93 both promote angiogenesis. METHODS AND RESULTS: Mice following hind‐limb ischemia (HLI) and ECs with, and without, hypoxia and serum starvation were examined with, and without, microRNA‐93 and VEGF(165)a. Post‐HLI perfusion recovery was monitored. EC metabolism was studied using seahorse assay, and the expression and activity of major metabolism genes were assessed. Reactive oxygen species levels and EC permeability were evaluated. C57Bl/6J mice generated a robust angiogenic response to HLI, with ECs from ischemic versus nonischemic muscle demonstrating no increase in glycolysis. Balb/CJ mice generated a poor angiogenic response post‐HLI; ischemic versus nonischemic ECs demonstrated significant increase in glycolysis. MicroRNA‐93‐treated Balb/CJ mice post‐HLI showed better perfusion recovery, with ischemic versus nonischemic ECs showing no increase in glycolysis. VEGF(165)a‐treated Balb/CJ mice post‐HLI showed no improvement in perfusion recovery with ischemic versus nonischemic ECs showing significant increase in glycolysis. ECs under hypoxia and serum starvation upregulated PFKFB3. In ECs under hypoxia and serum starvation, VEGF(165)a versus control significantly upregulated PFKFB3 and glycolysis, whereas miR‐93 versus control demonstrated no increase in PFKFB3 or glycolysis. MicroRNA‐93 versus VEGF(165)a upregulated glucose‐6‐phosphate dehydrogenase expression and activity, activating the pentose phosphate pathway. MicroRNA‐93 versus control increased reduced nicotinamide adenine dinucleotide phosphate and virtually eliminated the increase in reactive oxygen species. In ECs under hypoxia and serum starvation, VEGF(165)a significantly increased and miR‐93 decreased EC permeability. CONCLUSIONS: In peripheral artery disease, activation of the pentose phosphate pathway to promote angiogenesis may offer potential therapeutic advantages. John Wiley and Sons Inc. 2023-03-28 /pmc/articles/PMC10122893/ /pubmed/36974760 http://dx.doi.org/10.1161/JAHA.122.027986 Text en © 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Zaied, Abdelrahman A.
Ushio‐Fukai, Masuko
Fukai, Tohru
Kovacs‐Kasa, Anita
Alhusban, Suhib
Sudhahar, Varadarajan
Ganta, Vijay C.
Annex, Brian H.
Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title_full Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title_fullStr Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title_full_unstemmed Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title_short Pentose Pathway Activation Is Superior to Increased Glycolysis for Therapeutic Angiogenesis in Peripheral Arterial Disease
title_sort pentose pathway activation is superior to increased glycolysis for therapeutic angiogenesis in peripheral arterial disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122893/
https://www.ncbi.nlm.nih.gov/pubmed/36974760
http://dx.doi.org/10.1161/JAHA.122.027986
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