Inhalation of fine particulate matter air (PM) pollution (<2.5pm) is associated with an increased risk for cardiovascular disease (CVD) and Type 2 diabetes (T2D). Short-term exposure of mice to concentrated ambient air particulate matter (CAP) decreases vascular insulin sensivity and circulating endothelial progenitor cells (EPCs). EPCs are thought to be involved in endothelial maintenance, thus we propose that CAP-induced suppression of circulating and tissue-resident EPCs leads to endothelial injury and insulin resistance, which provokes systemic insulin resistance ultimatively increasing the risk for T2D and CVD. CAP exposure affects vascular health by triggering low-grade inflammation via Inflammasome activation. To elucidate both, mechanism(s) and causal relationship of endothelial injury, EPC depletion and vascular insulin resistance we will examine in the aim 1:1) whether CAP-exposure alone is sufficient to induce systemic insulin resistance or whether it only exacerbates the effects of obesity, and 2) the physico-chemical composition and body deposition of CAP to establish a more precise dosimetry and to find potential particle properties responsible for the biological effects. In our second aim we will investigate whether alterations in circulating/tissue resident EPCs and endothelial health are causative for the development of vascular insulin resistance. Finally, to find the mechanisms of CAP-induced vascular insulin resistance we will examine in aim 3 a possible role ofthe activation ofthe inflammasome. We will utilize a mouse model of diet-induced obesity (DIO) to investigate effects of HFD-feeding, and use mice deficient in NLRP3 and Casp-1 to test the contribution of Inflammasome activation in the development of vascular insulin resistance. Completion of these studies will provide novel insights into the mechanism(s) by which inhaled ambient particles increase the risk for T2D and CVD, and as such will provide unique and detailed information of particle dose, composition and deposition and their correlation with biological responses, which could lead to the development of novel biomarkers and strategies for the regulation of environmental pollutants and the prevention and management of insulin resistance, obesity, T2D and CVD.

Public Health Relevance

Environmental factors seem to enhance the rapid evolving epidemic of diabetes and obesity. In this project we will investigate a potential link between diabetes and air pollution by determine the role of inhaled PM on the development of vascular and systemic insulin resistance. This project will provide unparalleled findings that PM may cause diabetes, and could be the basis for future regulations, pre- and intervention strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-Y (C2))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
United States
Zip Code
Barnett, Rebecca Elise; Conklin, Daniel J; Ryan, Lindsey et al. (2016) Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis. J Leukoc Biol 99:361-71
Khan, Abdur Rahman; Farid, Talha A; Pathan, Asif et al. (2016) Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical Therapy: A Systematic Review and Meta-Analysis. Circ Res 118:984-93
Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul et al. (2016) Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem 291:13634-48
DeFilippis, Andrew P; Chernyavskiy, Ilya; Amraotkar, Alok R et al. (2016) Circulating levels of plasminogen and oxidized phospholipids bound to plasminogen distinguish between atherothrombotic and non-atherothrombotic myocardial infarction. J Thromb Thrombolysis 42:61-76
Conklin, Daniel J; Haberzettl, Petra; Jagatheesan, Ganapathy et al. (2016) Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein. Toxicol Appl Pharmacol :
Conklin, Daniel J (2016) Acute cardiopulmonary toxicity of inhaled aldehydes: role of TRPA1. Ann N Y Acad Sci 1374:59-67
Finch, Jordan; Conklin, Daniel J (2016) Air Pollution-Induced Vascular Dysfunction: Potential Role of Endothelin-1 (ET-1) System. Cardiovasc Toxicol 16:260-75
Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni et al. (2016) Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis. Am J Physiol Heart Circ Physiol 310:H1423-38
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Zhang, Michael J; Sansbury, Brian E; Hellmann, Jason et al. (2016) Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation 134:666-80

Showing the most recent 10 out of 64 publications