Benzene Exposure and Heart Failure

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Project Summary Long-term exposure air pollutant exposure is recognized as a risk factor for cardiovascular diseases including myocardial ischemia and heart failure. Recent epidemiological and experimental data indicate that many volatile organic compounds including benzene contribute to worsening outcomes in patients with progressive heart disease. Benzene is the most abundant air pollutant mostly generated from automobile exhaust and tobacco smoke. Despite high prevalence of benzene in air-pollutants, little is known about the direct effects of inhaled benzene on heart failure morbidity and mortality in well-controlled animal studies. Our recent studies show that benzene exposure resembling moderate to high levels of human exposure worsens cardiac function in pressure overload-induced mice. The benzene-induced worsening of cardiac functions was accompanied by endothelial activation and infiltration of granulocytes in the heart and upregulation of gene expression for CXCL1 chemokine and alarmin S100A8/A9 complex which promotes neutrophil and monocyte chemotaxis and adhesion through TLR4 and RAGE signaling. Our new preliminary data show that ambient benzene exposure causes endothelial activation/injury in humans and chronic low dose exposure stimulates endothelial activation/injury in mice. Using animal model of pressure overload-induced cardiac dysfunction, we will examine the effects of environmental benzene exposure on cardiac dysfunction (echocardiography, cardiac hypertrophy, analysis of composition and activation status of infiltrating immune cells) during heart remodeling (Aim 1), and examine the molecular mechanisms by which benzene exacerbate cardiac dysfunction (Aim 2). Successful completion of these studies will, for the first time, show how benzene affect cardiac function in patients with progressing heart failure and provide mechanistic insight into this process.