Increase of Palmitic Acid Concentration Impairs Endothelial Progenitor Cell and Bone Marrow–Derived Progenitor Cell Bioavailability

Abstract

Metabolic profiling of plasma nonesterified fatty acids discovered that palmitic acid (PA), a natural peroxisome proliferator–activated receptor γ (PPARγ) ligand, is a reliable type 2 diabetes biomarker. We investigated whether and how PA diabetic (d-PA) concentrations affected endothelial progenitor cell (EPC) and bone marrow–derived hematopoietic cell (BM-HC) biology. PA physiologic (n-PA) and d-PA concentrations were used. Proliferating cell nuclear antigen content and signal transducer and activator of transcription 5 (STAT5), PPARγ, cyclin D1, and p21Waf expression were evaluated. Small interfering RNA technology, gene reporter luciferase assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and coimmunoprecipitation were exploited. In vivo studies and migration assays were also performed. d-PA, unlike n-PA or physiological and diabetic oleic and stearic acid concentrations, impaired EPC migration and EPC/BM-HC proliferation through a PPARγ-mediated STAT5 transcription inhibition. This event did not prevent the formation of a STAT5/PPARγ transcriptional complex but was crucial for gene targeting, as p21Waf gene promoter, unlike cyclin D1, was the STAT5/PPARγ transcriptional target. Similar molecular events could be detected in EPCs isolated from type 2 diabetic patients. By expressing a constitutively activated STAT5 form, we demonstrated that STAT5 content is crucial for gene targeting and EPC fate. Finally, we also provide in vivo data that d-PA–mediated EPC dysfunction could be rescued by PPARγ blockade. These data provide first insights on how mechanistically d-PA drives EPC/BM-HC dysfunction in diabetes.

Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol

“…affects CAC pro-vascularizing characteristics without directly modifying viability, in contrast to what has been shown on late EPC[12][13][14] . High levels of PA decrease either gene and/or surface expressions of PECAM-1, CXCR4 and SDF1α, which may have major deleterious consequences in vivo, reducing CAC extravazation and recruitment of further pro-angiogenic cells through SDF1α release at the sites of injury.…”

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

“…PPARc and STAT5A form heterodimers that enhance transcription of cell cycle progression proteins specifically cyclin D1 and reduces the expression of cell cycle progression inhibitor p21. This decrease in STAT5A is responsible for the halted proliferation of EPCs induced by palmitic acid [160].…”

“…Stearic, a-linolenic and arachidonic acids induce apoptosis of cultured EPCs via a caspase-8-dependent mechanism [160]. Palmitic and linoleic acids inhibit EPCs adhesion, migration, proliferation, and vasculogenesis capabilities of EPCs in a dose-dependent manner via inhibition of eNOS.…”

Regulation of EPCs: The Gateway to Blood Vessel Formation

“…In a study by Dentelli and colleagues, IL-3 activated the transcription factor STAT5 in CFU-ECs promoting increased expression of PPAR and formation of a STAT5/PPAR heterodimer, which regulated cell cycle progression by controlling cyclin D1 expression [122]. This phenomenon was not seen via activation of PPAR with TZDs or the PPAR agonist, palmitic acid, which instead led to cell cycle arrest due to a lack of cyclin D1 transcription [122,123]. These data suggest that PPAR mediated proliferation can be modulated differently depending on the composition of ligand in the cellular environment.…”