title: Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.
abstract: Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution.
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky p0habe02@louisville.edu.
authors.forename: Petra
authors.initials: P
authors.lastname: Haberzettl
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: James P
authors.initials: JP
authors.lastname: McCracken
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Conklin
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D000067696:Ataxin-1 / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D059305:Diet, High-Fat; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000378:metabolism; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D007004:Hypoglycemic Agents; C587672:IL1B protein, mouse; D058847:Inflammasomes; D018836:Inflammation Mediators; D007328:Insulin; D020382:Interleukin-18; D053583:Interleukin-1beta; D016328:NF-kappa B; D052638:Particulate Matter; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D020170:Caspase 1
keywords: PM2.5; T2D; air pollution; endothelial progenitor cells; fine particulate matter; metformin; rosiglitazone; vascular insulin resistance