Hypertension (HTN) contributes disproportionately to the global burden of disease. In our prior application, we have provided evidence for an important link between particulate matter <2.5 mm (PM2.5) exposure and development of HTN. In this competitive renewal application, we propose to further investigate these links in the context of our findings that inflammation mediated sympathetic nervous system (SNS) activation in circumventricular organs (CVO) in the brain represent an integrative mechanism for PM2.5 induced HTN. Our hypothesis is consistent with an evolving shift in our understanding of the SNS as an arbitrator of acute tonal changes in HTN to a facilitator of chronic functional and structural changes via immune mechanisms. We propose to test this hypothesis in both animal models and humans as part of our established inter-disciplinary collaborative group.
In aim 1, we will investigate the time course, loci and impact of central nervous system (CNS) inflammation on BP with PM2.5 exposure conducted in a versatile aerosol concentration enrichment system (VACES) using C57/Bl6 and NFkB reporter mice. We will directly assess the impact of PM2.5 in exaggerating BP using a model of central SNS activation and also assess the impact of activating inflammation proximally on SNS activation on BP response to FA/PM2.5. Dose response studies and analysis of PM2.5 components responsible for HTN, will be performed in pre-disposed models.
In Aim 2, the role of central TLR activation in the CVO organs will be tested by deleting TNF receptor-associated factor (TRAF6), selectively in the CVO using UbcCre-TRAF6flox/flox(TRAF6pCNS) mice using Tamoxifen injected intra-cerebroventricularly (ICV), followed by exposure to FA/PM2.5. TRAF6 is a unique member of the TRAF family that functions at nodal points where signals induced via multiple TLRs converge. We will additionally distinguish between neuronal and glial cell specific role of TRAF6 in CNS inflammation in response to PM2.5.
In Aim 3, we will test the involvement of central SNS as a relevant pathway in humans, exposed to sub-acute time periods to ambient PM2.5, as part of a blinded randomized cross-over intervention. Our hypothesis is that Guanfacine an approved a2A agonist will obviate the association of ambient PM2.5 with 24-hour ambulatory systolic BP and SNS activity measured by HRV measures. Our experiments are highly relevant to continuing risk posed by air- pollution to people living in urbanized environments.

Public Health Relevance

Particulate matter air-pollution is a major cause of global cardiovascular morbidity and mortality. In our previous submission we have demonstrated that a major component of air-pollution (particulate matter <2.5 ? micron in size (PM2.5) contributes to increases in blood pressure in both animals and humans. In this continuation grant we will investigate broad integrative mechanisms by which PM2.5 may facilitate development of hypertension and thereby contribute to cardiovascular events. We propose to test this association in novel animal models of susceptibility that mirror the human condition. We will also test the effect of a drug called Guanfacine in susceptible humans to see if this intervention can prevent increases in blood pressure associated with elevated levels of personal PM2.5 exposure.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Schug, Thaddeus
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ying, Zhekang; Allen, Katryn; Zhong, Jixin et al. (2016) Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. Inhal Toxicol 28:155-63
Brook, Robert D; Sun, Zhichao; Brook, Jeffrey R et al. (2016) Extreme Air Pollution Conditions Adversely Affect Blood Pressure and Insulin Resistance: The Air Pollution and Cardiometabolic Disease Study. Hypertension 67:77-85
Zhong, Jixin; Allen, Katryn; Rao, Xiaoquan et al. (2016) Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. Inhal Toxicol 28:383-92
Ying, Zhekang; Chen, Minjie; Xie, Xiaoyun et al. (2016) Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling. PLoS One 11:e0148305
Rao, Xiaoquan; Montresor-Lopez, Jessica; Puett, Robin et al. (2015) Ambient air pollution: an emerging risk factor for diabetes mellitus. Curr Diab Rep 15:603
Morishita, Masako; Bard, Robert L; Wang, Lu et al. (2015) The characteristics of coarse particulate matter air pollution associated with alterations in blood pressure and heart rate during controlled exposures. J Expo Sci Environ Epidemiol 25:153-9
Zheng, Ze; Zhang, Xuebao; Wang, Jiemei et al. (2015) Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models. J Hepatol 63:1397-404
Morishita, Masako; Bard, Robert L; Kaciroti, Niko et al. (2015) Exploration of the composition and sources of urban fine particulate matter associated with same-day cardiovascular health effects in Dearborn, Michigan. J Expo Sci Environ Epidemiol 25:145-52
Zhong, Jixin; Maiseyeu, Andrei; Rajagopalan, Sanjay (2015) Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. Clin Lipidol 10:103-112
Hogan, Matthew K; Kovalycsik, Taylor; Sun, Qinghua et al. (2015) Combined effects of exposure to dim light at night and fine particulate matter on C3H/HeNHsd mice. Behav Brain Res 294:81-8

Showing the most recent 10 out of 60 publications