Libang Yang1, Ling Gao1, Thomas Nickel1, Jing Yang1, Jingyi Zhou1, Adam Gilbertsen1, Zhaohui Geng1, Caitlin Johnson1, Bernice Young1, Craig Henke1, Glenn R Gourley1, Jianyi Zhang2. 1. From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China. 2. From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China. jayzhang@uab.edu.
Abstract
RATIONALE: The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. OBJECTIVE: To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. METHODS AND RESULTS: Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L-) medium. Compared with the L- medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues. CONCLUSIONS: These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.
RATIONALE: The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. OBJECTIVE: To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. METHODS AND RESULTS: Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L-) medium. Compared with the L- medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues. CONCLUSIONS: These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.
Authors: Tiago C Leite; Raquel G Coelho; Daniel Da Silva; Wagner S Coelho; Monica M Marinho-Carvalho; Mauro Sola-Penna Journal: FEBS Lett Date: 2010-11-11 Impact factor: 4.124
Authors: Libang Yang; Kyle D Rudser; LeeAnn Higgins; Hugo R Rosen; Atif Zaman; Christopher L Corless; Larry David; Glenn R Gourley Journal: Dig Dis Sci Date: 2011-05-17 Impact factor: 3.199
Authors: Oscar R Colegio; Ngoc-Quynh Chu; Alison L Szabo; Thach Chu; Anne Marie Rhebergen; Vikram Jairam; Nika Cyrus; Carolyn E Brokowski; Stephanie C Eisenbarth; Gillian M Phillips; Gary W Cline; Andrew J Phillips; Ruslan Medzhitov Journal: Nature Date: 2014-07-13 Impact factor: 69.504
Authors: Elizabeth R Axton; Laura M Beaver; Lindsey St Mary; Lisa Truong; Christiana R Logan; Sean Spagnoli; Mary C Prater; Rosa M Keller; Manuel Garcia-Jaramillo; Sarah E Ehrlicher; Harrison D Stierwalt; Sean A Newsom; Matthew M Robinson; Robert L Tanguay; Jan F Stevens; Norman G Hord Journal: J Nutr Date: 2019-12-01 Impact factor: 4.798