Air pollution has long been associated with an increased risk of cardiovascular disease, however the exact mechanisms that underlie the pathogenesis of air pollution induced myocardial infarction remain incompletely understood. Although numerous studies have examined vascular effects as the primary cause of myocardial injury, only a few studies have investigated for direct toxic effects of inhaled pollutants on myocardial cells. Some of these studies have suggested an increased incidence of myocardial apoptosis and fibrosis after experimental exposure, raising the possibility that some of the arrhythmogenic and myopathic effects seen in clinical populations may ensue from direct myocardial injury. Accordingly, we propose the following specific aims:
Aim 1 : Determine whether exposure to diesel exhaust (DE) predisposes to hypertrophy, heart failure, apoptosis, fibrosis and myocardial infarction in vivo and in vitro in experimental mouse models. We will expose wild type mice to diesel exhaust and then assess for LV function and cardiac hypertrophy. We will also assess for apoptosis and fibrosis and will challenge exposed mice with hypertrophic stimuli to determine whether the mice are predisposed to hypertrophy and heart failure after exposure.
Aim 2 : Determine whether CHF1/Hey2, an important regulator of myocardial hypertrophy and heart failure, affects the pathological response to diesel exhaust. We propose to examine whether myocardial CHF1/Hey2 expression is altered in experimental animals exposed to diesel exhaust, and then will evaluate whether loss of function or gain of function in mice can alter their experimental response to diesel exhaust.
Aim 3 : Determine whether serum-borne mediators in exposed animals and patients induce myocardial toxicity and identify potential diesel exhaust-induced transcriptional mechanisms. We will treat cultured myocytes from unexposed animals with serum from exposed animals and patients and measure cellular hypertrophy and apoptosis, to determine whether there are soluble mediators in exposed patient serum that predispose to either of these pathological processes. The transcriptional basis for alteration in hypertrophic or apoptotic responses would be further examined by genomic analysis.
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