Chronic Hyperuricemia Impairs Blood Flow Recovery in the Ischemic Hindlimb through Suppression of Endothelial Progenitor Cells
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// I-Chun Chen 1 , Chin-Sung Kuo 1, 2 , Chih-Cheng Wu 3, 4, 5, 6 , Hsiao-Ya Tsai 1 , Chih-Pei Lin 7, 8 , Szu-Yuan Li 1, 9 , Ruey-Hsing Chou 1, 3, 10 , Po-Hsun Huang 1, 3, 10 , Jaw-Wen Chen 3, 10, 11, 12 and Shing-Jong Lin 1, 3, 10, 11, 13 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 2 Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 3 Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan 4 National Tsing-Hua University, Institute of Biomedical Engineering, Hsinchu, Taiwan 5 National Taiwan University Hospital, College of Medicine, Taipei, Taiwan 6 Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan 7 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 8 Department of Biotechnology and Laboratory Science in Medicine and Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan 9 Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 10 Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 11 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 12 Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan 13 Taipei Medical University, Taipei, Taiwan Correspondence to: Po-Hsun Huang, email: huangbsvgh@gmail.com Chih-Cheng Wu, email: chihchengwumd@gmail.com Chin-Sung Kuo, email: cskuo241@yahoo.com.tw Keywords: hyperuricemia; endothelial progenitor cell; ischemia; neovascularization Received: August 14, 2017 Accepted: January 02, 2018 Published: January 22, 2018 ABSTRACT Objective: Chronic hyperuricemia is associated with cardiovascular disease, but its impact on endothelial progenitor cells (EPC) and ischemia-induced neovascularization remains unclear. Herein we investigated whether chronic hyperuricemia could impede blood flow recovery in response to tissue ischemia by suppression of EPC. Methods: Human EPC were isolated and cultured in a high-level uric acid medium for functional testing. Cell proliferation, nitric oxide (NO) production and apoptosis assay were examined. A chronic hyperuricemia mouse model was established by potassium oxonate treatment and/or a high-level uric acid diet to evaluate the actions of chronic hyperuricemia on ischemia-induced blood flow recovery. After 4 weeks of drug treatment, hindlimb ischemia surgery was performed in the control and hyperuricemia mice. Blood flow recovery was followed up every week before and after ischemic surgery using a laser Doppler Perfusion Imager System. The circulating EPC number in the peripheral blood was determined by flow cytometry (Sca-1 + /Flk-1 + ). Results: Incubation with a high-level uric acid medium (10 mg/dL) significantly suppressed EPC proliferation, reduced NO production, and lessened phosphorylation of Akt and eNOS. Moreover, EPC treated with high-level uric acid increased reactive oxygen species production, promoted cellular apoptosis and senescence, and also inhibited EPC tube formation. Four weeks after hindlimb ischemia surgery, the chronic hyperuricemia mice had significantly reduced tissue reperfusion, EPC mobilization, and impaired neovascularization in the ischemic hindlimbs compared with the control mice. Conclusions: Chronic hyperuricemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC.
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In vitro studies reported increased cellular senescence and enhanced ROS production in endothelial progenitor cells cultured in medium containing UA at high concentrations (10 mg/dL).
“Further, in vitro studies have reported an increased cellular senescence and enhanced ROS production in endothelial progenitor cells cultured in a medium containing UA at high concentrations (10 mg/dL) [223].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [223]
UA triggers OS-induced senescence through inhibition of eNOS, which is essential to produce the scavenging molecule NO.
“At the molecular level, there is evidence that UA triggers OS-induced senescence through the inhibition of the enzyme eNOS, which is essential to produce the scavenging molecule NO [215,223].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [223]
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Cites
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., & Zeiher, A. M. (1999) · Nature · doi:10.1038/21224 · Cited by 3,591 · see citing works
Circulating endothelial progenitor cells, vascular function, and cardiovascular risk
Hill, J. M., Zalos, G., Halcox, J. P. J., Schenke, W. H., Waclawiw, M. A., Quyyumi, A. A., & Finkel, T. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022287 · Cited by 3,423 · see citing works
Asahara, T., Masuda, H., Takahashi, T., Kalka, C., Pastore, C., Silver, M., Kearne, M., Magner, M., & Isner, J. M. (1999) · Circulation Research · doi:10.1161/01.res.85.3.221 · Cited by 3,249 · see citing works
Uric Acid and Cardiovascular Risk
Feig, D. I., Kang, D., & Johnson, R. J. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0800885 · Cited by 2,443 · see citing works
Takahashi, T., Kalka, C., Masuda, H., Chen, D., Silver, M., Kearney, M., Magner, M., Isner, J. M., & Asahara, T. (1999) · Nature Medicine · doi:10.1038/7434 · Cited by 2,421 · see citing works
Molecular mechanisms of caspase regulation during apoptosis
Riedl, S. J., & Shi, Y. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1496 · Cited by 1,893 · see citing works
Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization
Kalka, C., Masuda, H., Takahashi, T., Kalka-Moll, W. M., Silver, M., Kearney, M., Li, T., Isner, J. M., & Asahara, T. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3422 · Cited by 1,862 · see citing works
Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells
Aicher, A., Heeschen, C., Mildner-Rihm, C., Urbich, C., Ihling, C. H., Technau‐Ihling, K., Zeiher, A. M., & Dimmeler, S. (2003) · Nature Medicine · doi:10.1038/nm948 · Cited by 1,297 · see citing works
Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.
Murohara, T., Asahara, T., Silver, M., Bauters, C., Masuda, H., Kalka, C., Kearney, M., Chen, D., Symes, J. F., Fishman, M. C., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1560 · Cited by 1,201 · see citing works
Self-citationHyperuricemia induces endothelial dysfunction
Khosla, U. M., Zharikov, S. I., Finch, J., Nakagawa, T., Roncal, C., Mu, W., Krotova, K. Y., Block, E. R., Prabhakar, S. S., & Johnson, R. J. (2005) · Kidney International · doi:10.1111/j.1523-1755.2005.00273.x · Cited by 1,197 · see citing works
Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction
Aßmus, B., Honold, J., Schächinger, V., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa051779 · Cited by 1,040 · see citing works
Richette, P., & Bardin, T. (2010) · The Lancet · doi:10.1016/s0140-6736(09)60883-7 · Cited by 915 · see citing works
Sautin, Y. Y., Nakagawa, T., Zharikov, S. I., & Johnson, R. J. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00600.2006 · Cited by 789 · see citing works
Corry, D. B., Eslami, P., Yamamoto, K., Nyby, M. D., Makino, H., & Tuck, M. L. (2008) · Journal of Hypertension · doi:10.1097/hjh.0b013e3282f240bf · Cited by 750 · see citing works
Yu, M.-A., Sánchez-Lozada, L. G., Johnson, R. J., & Kang, D.-H. (2010) · Journal of Hypertension · doi:10.1097/hjh.0b013e328337da1d · Cited by 626 · see citing works
Uric acid and inflammatory markers
Ruggiero, C., Cherubini, A., Blè, A., Bós, Â. J. G., Maggio, M. G., Dixit, V. D., Lauretani, F., Bandinelli, S., Senin, U., & Ferrucci, L. (2006) · European Heart Journal · doi:10.1093/eurheartj/ehi879 · Cited by 595 · see citing works
Hyperuricemia in Primary and Renal Hypertension
Cannon, P., Stason, W. B., Demartini, F. E., Sommers, S. C., & Laragh, J. H. (1966) · New England Journal of Medicine · doi:10.1056/nejm196609012750902 · Cited by 508 · see citing works
Bone Marrow–Derived Progenitor Cells Modulate Vascular Reendothelialization and Neointimal Formation
Werner, N., Priller, J., Laufs, U., Endres, M., Böhm, M., Dirnagl, U., & Nickenig, G. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000036417.43987.d8 · Cited by 432 · see citing works
Lehto, S., NISKANEN, L. K., Rönnemaa, T., & Laakso, M. (1998) · Stroke · doi:10.1161/01.str.29.3.635 · Cited by 411 · see citing works
Oxidative Stress in Diabetes: Implications for Vascular and Other Complications
Pitocco, D., Tesauro, M., Rizzi, A., Ghirlanda, G., & Cardillo, C. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141121525 · Cited by 409 · see citing works
Uric acid: A marker of increased cardiovascular risk
Gagliardi, A. C. M., Miname, M. H., & Santos, R. D. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.05.022 · Cited by 386 · see citing works
Dernbach, E., Urbich, C., Brandes, R. P., Hofmann, W. K., Zeiher, A. M., & Dimmeler, S. (2004) · Blood · doi:10.1182/blood-2003-12-4103 · Cited by 331 · see citing works
Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia
Sánchez‐Lozada, L. G., Soto, V., Tapia, E., Ávila-Casado, C., Sautin, Y. Y., Nakagawa, T., Franco, M., Rodríguez‐Iturbe, B., & Johnson, R. J. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00104.2008 · Cited by 310 · see citing works
Waltenberger, J. L. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(00)00228-5 · Cited by 310 · see citing works
Inactivation of Nitric Oxide by Uric Acid
Gersch, C. M., Palii, S. P., Kim, K. M., Angerhofer, A., Johnson, R. J., & Henderson, G. N. (2008) · Nucleosides Nucleotides & Nucleic Acids · doi:10.1080/15257770802257952 · Cited by 254 · see citing works
He, T., Peterson, T. E., Holmuhamedov, E., Terzic, A., Caplice, N. M., Oberley, L. W., & Katušić, Z. S. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000142810.27849.8f · Cited by 238 · see citing works
Zharikov, S. I., Krotova, K. Y., Hu, H., Baylis, C., Johnson, R. J., Block, E. R., & Patel, J. M. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00075.2008 · Cited by 238 · see citing works
Modulating the Vascular Response to Limb Ischemia
Cooke, J. P., & Losordo, D. W. (2015) · Circulation Research · doi:10.1161/circresaha.115.303565 · Cited by 219 · see citing works
Sex differences in uric acid and risk factors for coronary artery disease
Tuttle, K. R., Short, R., & Johnson, R. J. (2001) · The American Journal of Cardiology · doi:10.1016/s0002-9149(01)01566-1 · Cited by 174 · see citing works
Mukherjee, S., Ghosh, S., Choudhury, S., Adhikary, A., Manna, K., Dey, S., Sa, G., Das, T., & Chattopadhyay, S. (2013) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2013.07.005 · Cited by 149 · see citing works
Serum uric acid and brain ischemia in normal elderly adults
Schretlen, D. J., Inscore, A. B., Vannorsdall, T. D., Kraut, M. A., Pearlson, G. D., Gordon, B., & Jinnah, H. A. (2007) · Neurology · doi:10.1212/01.wnl.0000277468.10236.f1 · Cited by 135 · see citing works
Urbich, C., Reissner, A., Chavakis, E., Dernbach, E., Haendeler, J., Fleming, I., Zeiher, A. M., Kaszkin, M., & Dimmeler, S. (2002) · The FASEB Journal · doi:10.1096/fj.01-0637fje · Cited by 130 · see citing works
Park, J., Jin, Y. M., Hwang, S., Cho, D., Kang, D., & Jo, I. (2013) · Nitric Oxide · doi:10.1016/j.niox.2013.04.003 · Cited by 116 · see citing works
Papežíková, I., Pekarová, M., Kolářová, H., Klinke, A., Lau, D., Baldus, S. E., Lojek, A., & Kubala, L. (2012) · Free Radical Research · doi:10.3109/10715762.2012.747677 · Cited by 102 · see citing works
Uric Acid Heralds Ischemic Tissue Injury to Mobilize Endothelial Progenitor Cells
Patschan, D., Patschan, S. A., Gobe, G. G., et al. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070759 · Cited by 97 · see citing works
Chao, H., Liu, J., Lin, J., Chen, C., Wu, C., & Cheng, T.-H. (2008) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2008.00877.x · Cited by 79 · see citing works
Self-citationWeihrauch, D., Lohr, N. L., Mraović, B., et al. (2004) · Circulation · doi:10.1161/01.cir.0000129225.67353.1f · Cited by 78 · see citing works
Schwartz, I. F., Grupper, A., Chernichovski, T., Grupper, A., Hillel, O., Engel, A., & Schwartz, D. (2010) · Journal of Vascular Research · doi:10.1159/000320356 · Cited by 61 · see citing works
Chen, J., Jing, J., Yu, S., Song, M., Tan, H., Cui, B., & Huang, L. (2016) · PubMed Central · Cited by 59 · see citing works
Self-citationTsai, H., Lin, C.-P., Huang, P.-H., Li, S., Chen, J.-S., Lin, F., Chen, J., & Lin, S. (2015) · Journal of Diabetes Research · doi:10.1155/2016/6384759 · Cited by 40 · see citing works
Self-citationChiu, C.-C., Chen, Y., Hsu, C., et al. (2016) · Scientific Reports · doi:10.1038/srep26541 · Cited by 29 · see citing works
Sun, P., Ye, L., MASON, M. D., & Jiang, W. G. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.2082 · Cited by 20 · see citing works
Effects of Cardiovascular Risk Factors on Endothelial Progenitor Cell.
Huang, P.-H., Chen, J., & Lin, S. (2014) · PubMed Central · Cited by 16 · see citing works
Self-citationUric acid: A crucial marker of cardiovascular diseases?
Yıldız, A., & Kaya, Z. (2012) · International Journal of Cardiology · doi:10.1016/j.ijcard.2012.05.054 · Cited by 8 · see citing works
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
- Authors
- Chen, I.-C., Kuo, C.-S., Wu, C.-C., Tsai, H.-Y., Lin, C.-P., Li, S.-Y., Chou, R.-H., Huang, P.-H., Chen, J.-W., & Lin, S.-J.
- Affiliations
- National Yang Ming University (TW)
- Taipei Veterans General Hospital (TW)
- National Tsing Hua University (TW)
- Corresponding author
- Wu, Chih-Cheng
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2018-01-22
- Volume
- 9
- Issue
- 10
- Pages
- 9285-9298
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5823617
- OpenAlex
- W2791859505
- Cited by
- 11
- References
- 44
- Citations by year
- 2023: 4 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Taiwan University Hospital
- National Taiwan University
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- endothelial progenitor cells, hindlimb ischemia, blood flow recovery, neovascularization, uric acid, angiogenesis, oxidative stress, nitric oxide synthase, nitric oxide, reactive oxygen species, endothelial dysfunction
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