PMID- 35142393 OWN - NLM STAT- MEDLINE DCOM- 20220304 LR - 20230302 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 36 IP - 3 DP - 2022 Mar TI - Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3. PG - e22177 LID - 10.1096/fj.202101323R [doi] AB - Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O(2)(*-) to H(2) O(2) whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3(-/-) mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H(2) O(2) levels in a heparin-binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3(-/-) mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease. CI - (c) 2022 Federation of American Societies for Experimental Biology. FAU - Abdelsaid, Kareem AU - Abdelsaid K AUID- ORCID: 0000-0002-5759-4714 AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA. FAU - Sudhahar, Varadarajan AU - Sudhahar V AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA. AD - Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Harris, Ryan A AU - Harris RA AD - Georgia Prevention Institute, Augusta, Georgia, USA. FAU - Das, Archita AU - Das A AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Youn, Seock-Won AU - Youn SW AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois, USA. FAU - Liu, Yutao AU - Liu Y AD - Department of Cell Biology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - McMenamin, Maggie AU - McMenamin M AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Hou, Yali AU - Hou Y AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Fulton, David AU - Fulton D AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Hamrick, Mark W AU - Hamrick MW AD - Department of Cell Biology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Tang, Yaoliang AU - Tang Y AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Fukai, Tohru AU - Fukai T AUID- ORCID: 0000-0001-9864-571X AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA. AD - Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. FAU - Ushio-Fukai, Masuko AU - Ushio-Fukai M AUID- ORCID: 0000-0001-7048-2381 AD - Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. AD - Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, Georgia, USA. LA - eng GR - R01 HL160014/HL/NHLBI NIH HHS/United States GR - R01 HL135584/HL/NHLBI NIH HHS/United States GR - R01 HL147550/HL/NHLBI NIH HHS/United States GR - R01 HL133613/HL/NHLBI NIH HHS/United States GR - R01 HL116976/HL/NHLBI NIH HHS/United States GR - R01 HL134354/HL/NHLBI NIH HHS/United States GR - R01 HL070187/HL/NHLBI NIH HHS/United States GR - I01 BX001232/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Atp7a protein, mouse) RN - EC 1.15.1.1 (Sod3 protein, mouse) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 7.2.2.8 (Copper-Transporting ATPases) SB - IM MH - Animals MH - Cells, Cultured MH - Copper-Transporting ATPases/blood/metabolism MH - Diabetes Mellitus, Type 2/*metabolism/physiopathology MH - Endothelium, Vascular/metabolism/physiology MH - Exercise MH - Exosomes/*metabolism MH - Female MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - *Neovascularization, Physiologic MH - Physical Conditioning, Animal/methods MH - Rats MH - *Running MH - Superoxide Dismutase/blood/*metabolism PMC - PMC8880294 MID - NIHMS1772145 OTO - NOTNLM OT - SOD3 OT - exercise OT - exosome OT - type 2 diabetes COIS- DISCLOSURES The authors declare no competing financial interests. EDAT- 2022/02/11 06:00 MHDA- 2022/03/05 06:00 PMCR- 2023/03/01 CRDT- 2022/02/10 08:38 PHST- 2021/12/29 00:00 [revised] PHST- 2021/08/21 00:00 [received] PHST- 2022/01/07 00:00 [accepted] PHST- 2022/02/10 08:38 [entrez] PHST- 2022/02/11 06:00 [pubmed] PHST- 2022/03/05 06:00 [medline] PHST- 2023/03/01 00:00 [pmc-release] AID - 10.1096/fj.202101323R [doi] PST - ppublish SO - FASEB J. 2022 Mar;36(3):e22177. doi: 10.1096/fj.202101323R.