Although numerous advancements made in the field of human health have resulted in reduced deaths due to cardiovascular diseases (CVD), many patients with cardiac disease show no established risk. Therefore, other unknown factors may be responsible for the pathophysiology of CVD. Out of 350,000 sudden cardiac deaths each year in the United States, 60,000 deaths have been related to air pollution, suggesting a detrimental role of environmental pollutants in the development of CVD. The present study tested our hypothesis that chronic ozone exposure enhances the sensitivity to ischemia-reperfusion (I/R) injury in isolated perfused hearts. Sprague-Dawley rats were continuously exposed for 8 h/day for 28 and 56 days to filtered air or 0.8 ppm ozone. Isolated hearts were subjected to 30 min of global ischemia followed by 60 min of reperfusion. Cardiac function after I/R measured as left ventricular developed pressure (LVDP), +dP/dt, -dP/dt, and left ventricular end diastolic pressure (LVEDP) was significantly decreased and increased respectively in ozone-exposed I/R hearts compared to I/R hearts exposed to filtered air. The enhanced sensitivity to I/R injury upon ozone exposure was associated with increased myocardial TNF-alpha levels and lipid peroxidation and decreased myocardial activities of superoxidase dismutase (SOD) and IL-10. These data suggest that ozone-induced sensitivity to myocardial I/R injury may be due to promoting levels of oxidative stress as well as inflammatory mediators.

A number of advancements have been made toward identifying the risk factors associated with cardiovascular disease (CVD) and have resulted in a decline in mortality. However, many patients with cardiac disease show no established previous risk. Thus, it appears that other unknown factors contribute to the pathophysiology of CVD. Out of 350,000 sudden cardiac deaths each year in the United States, 60,000 deaths have been linked to air pollution, suggesting a detrimental role of environmental pollutants in the development of CVD. This study tested the hypothesis that chronic ozone (O(3)) exposure diminishes myocardial function in healthy population. Male Sprague-Dawley rats were exposed 8 h/day for 28 and 56 days to filtered air or 0.8 ppm O(3). In vivo cardiac function was assessed by measuring LVDP, +dP/dt, -dP/dt, and LVEDP 24 h after termination of the O(3) exposure. Compared to rats exposed to filtered air, LVDP, +dP/dt, and -dP/dt were significantly decreased, and LVEDP was significantly increased in O(3) exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-alpha levels and lipid peroxidation as well as decreased myocardial activities of superoxidase dismutase and interleukin-10 levels. These novel findings suggest myocardial dysfunction subsequent to chronic O(3) exposure in normal adult rats may be associated with a decrease in antioxidant reserve and with an increased production of inflammatory mediators.

Earlier studies from our laboratory have shown myocardial dysfunction subsequent to chronic O(3) exposure in rats may be associated with a decrease in antioxidant reserve and increased activity of inflammatory mediators. The present study tested the hypothesis that O(3)-induced cardiac dysfunction in healthy adult rats may be due to changes in caveolin-1 and caveolin-3 levels. Sprague-Dawley rats were exposed 8 h/day for 28 and 56 days to filtered air or 0.8 ppm O(3). In order to assess the chronic effects to O(3), in vivo cardiac function was assessed by measuring LVDP, 24 h after termination of O(3) exposure. Compared to rats exposed to filtered air, LVDP values significantly decreased in all O(3)-exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-α levels and decreased myocardial activities of superoxidase dismutase. Progressive increases in the expression of myocardial TNF-α in 28 days and 56 days O(3)-exposed animals were followed by decreases in cardiac caveolin-1 levels. On the other hand, differential changes in the expression of caveolin-3 in hearts from 28 and 56 days O(3)-exposed animals were independent of intra-cardiac TNF-α levels. These novel findings suggest the interesting possibility that a balance between caveolin-1 and caveolin-3 may be involved in O(3)-mediated cardiac toxicity.

Sex related differences have been noted in cardiovascular disease where females have a lower incidence of heart failure, and a higher rate of heart failure survival. On-the-other-hand, some studies have reported increased mortality in women compared with men. Recent data also suggest that women have an increased risk of death due to O 3 air pollution, which is in contrast to reports that short-term variations in gaseous pollutants are associated with an increase in hospitalization for cardiac disease that is not modified by gender. It has been speculated that because of the nature of the photochemical equilibrium of O 3 in the ambient environment and due to other confounding factors epidemiological investigations of the health effects of O 3 may be using O 3 as an exposure surrogate for other oxidants or co-pollutants, some of which may be interfering with response to O 3 . The present study in a controlled exposure protocol tested the hypothesis that female rats compared to male have decreased sensitivity to cardiac injury subsequent to O 3 exposure. Age matched male/female rats were exposed 8 hrs/day for 28 and 56 days to filtered air or 0.8 ppm O 3 . In order to assess the chronic effects to O 3 , in-vivo cardiac function was assessed, 24 hrs after termination of the O 3 exposure. Compared to female rats, LVDP values significantly decreased in O 3 exposed male rats. This enhanced attenuation of cardiac function in male animals was associated with increased myocardial TNF-alpha (TNF-α) levels and decreased myocardial activities of superoxidase dismutase (SOD). These novel findings suggest that decreased attenuation of cardiac function in O 3 exposed females compared to males exposed to similar conditions was associated with decreased inflammatory mediator production and decreased oxidative stress. Identifying the underlying factors for gender based variations in ozone response is very important to recognize at-risk groups who would benefit from preventive strategies. In addition identification of those at risk, their degree of sensitivity will assist with the cost-benefit analysis of “safe” exposure levels in the public health setting. The long-term goal of this study is in guiding regulatory policies for reduced environmental related health costs.

A significant number of deaths each year in the US have been linked to environmental pollutants such as ozone (O 3 ). Earlier studies from our laboratory have shown that myocardial dysfunction, subsequent to chronic O 3 exposure, in normal adult rats may be associated with a decrease in antioxidant reserve and with an increased activity of inflammatory mediators. The present study tested the hypothesis that O 3 induced cardiac dysfunction in healthy normal adult rats may be due to changes in caveolin-1 and caveolin-3 levels. Sprague Dawley rats were exposed 8 hr/day for 28 and 56 days to filtered air or 0.8 ppm O 3 . In order to assess the chronic effects to O 3 , in-vivo cardiac function was assessed by measuring left ventricular developed pressure (LVDP), 24 hr after termination of O 3 exposure. Compared to rats exposed to filtered air, LVDP values significantly decreased in all O 3 exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-alpha (TNF-α) levels and decreased myocardial activities of superoxidase dismutase (SOD). Progressive increases in the expression of myocardial TNF-α in 4 and 8 week O 3 exposed animals were followed by decreases in cardiac caveolin-1 levels. However, differential changes in the expression of caveolin-3 in hearts from 4 and 8 week O 3 exposed animals were independent of intra-cardiac TNF-α levels. These novel findings suggest the interesting possibility that a balance between caveolin-1 and caveolin-3 may be involved in O 3 - mediated cardiac toxicity. Furthermore, differential changes in caveolin-3 content may serve as a marker that predicts moderate and chronic stages of cardiac injury specific to exposure to O 3 in human populations residing in urban areas with unhealthy levels of O 3 . The study is timely and has clinical significance related to environmental causes of cardiovascular disease. This novel study will form a basis for future studies to understand and define the various components of the mechanistic cascade responsible for generation of cell death signaling subsequent to O 3 exposure. The long-term goal of this study is in guiding regulatory policies to the USEPA regarding air quality standards pertaining to O 3 levels.