Epidemiologic studies have clearly shown an increase in cardiopulmonary deaths in heavily polluted cities. We have recently shown that long-term exposure to PM2.5 causes systolic and diastolic dysfunction in vivo. This contradicts the current belief that heart dysfunction caused by PM2.5 is due to cytokine release from the lung. It is therefore not known whether the heart is directly affected by PM2.5, or if other mediators are released from the lung, and possibly through reactive oxygen species release, have an effect on the whole heart and isolated cardiomyocyte. It is clear that ambient air particulate matter (e.g., air pollution) and obesity are now major contributors to cardiovascular disease in western societies. It is also evident that these two stressors to the cardiovascular system may interact to enhance toxicities and worsen outcomes. This project is designed to address these potential interactions, at the specific level of cardiac muscle function. This hypothesis will be tested in in vivo (e.g., leptin-deficient ob/ob obese mice alone and crossed with MnSOD or p47phox transgenic mice and their heterozygous (lean) littermates) and in vitro (e.g., isolated cardiomyocytes from these mice) to determine the synergistic effect of PM2.5 exposure and obesity on cardiovascular risk, as well as the role of ROS in this dysfunction. While it is clear that PM2.5 exposure and obesity both play central roles in the pathogenesis of heart dysfunction, there is a major void in the understanding of the mechanisms that mediate the actions of these regulators. Echocardiography and pressure-volume loops will be used to assess global cardiovascular function. Mechanical function and calcium transient properties of isolated ventricular myocytes will be analyzed by video-based edge detection and fluorescence microscopy as the primary bioassays for assessing the impact of PM2.5 on heart function. Real-time RT-PCR and commercially available ELISA kits will be used to detect mechanisms leading to ROS production, along with post-translational modification and proteomic approaches. The goals of this investigation are to define the physiological and molecular effects of clinically-relevant concentrations of PM2.5 on the intact myocardium and the cardiomyocyte, and to determine the role of these particles on CV function in obesity.
The Aims to be tested include:
Aim #1 : Determine whether ROS-dependent mechanisms mediate PM2.5 exposure-induced LV contractile dysfunction in lean mice and exacerbate contractile dysfunction in obese mice.
Aim 2 : Define the molecular mechanisms that mediate ROS-induced cardiomyocyte dysfunction following PM2.5 exposure in lean and obese ob/ob mice. With these experiments, we hope to better define the mechanisms of PM2.5 exposure in the pathogenesis of heart dysfunction associated with obesity.
This R01 is designed to test the hypothesis that exposure to PM2.5 depresses CV function via oxidant-mediated pathways in lean animals and will exacerbate obesity-related CV complications by further enhancing oxidative stress.
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