Environmentally persistent free radicals decrease cardiac function before and after ischemia/reperfusion injuryin vivo

Abstract

Exposure to airborne particles is associated with increased cardiovascular morbidity and mortality. During the combustion of chlorine-containing hazardous materials and fuels, chlorinated hydrocarbons chemisorb to the surface of transition metal-oxide-containing particles, reduce the metal, and form an organic free radical. These radical-particle systems can survive in the environment for days and are called environmentally persistent free radicals (EPFRs). This study determined whether EPFRs could decrease left ventricular function before and after ischemia and reperfusion (I/R) in vivo. Male Brown Norway rats were dosed (8 mg/kg, i.t.) 24 hr prior to testing with particles containing the EPFR of 1, 2-dichlorobenzene (DCB230). DCB230 treatment decreased systolic and diastolic function. DCB230 also produced pulmonary and cardiac inflammation. After ischemia, systolic, but not diastolic function was significantly decreased in DCB230-treated rats. Ventricular function was not affected by I/R in control rats. There was greater oxidative stress in the heart and increased 8-isoprostane (biomarker of oxidative stress) in the plasma of treated vs control rats after I/R. These data demonstrate for the first time that DCB230 can produce inflammation and significantly decrease cardiac function at baseline and after I/R in vivo. Furthermore, these data suggest that EPFRs may be a risk factor for cardiac toxicity in healthy individuals and individuals with ischemic heart disease. Potential mechanisms involving cytokines/chemokines and/or oxidative stress are discussed.

Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

“…Inhalation of environmentally persistent free radicals, potentially derived from combustion of chlorine-containing hydrocarbons in rats, also caused cardiac inflammation and loss of function (29). These studies proposed a role for particulate matter-induced cardiovascular inflammation and oxidative stress (29). Cardiac effects of chlorine, especially cardiomegaly, were reported in autopsies of human victims of acute high-concentration chlorine gas exposure (1,(22)(23)(24).…”

“…Inhalation of environmentally persistent free radicals, potentially derived from combustion of chlorine-containing hydrocarbons in rats, also caused cardiac inflammation and loss of function (29). These studies proposed a role for particulate matter-induced cardiovascular inflammation and oxidative stress (29).…”

Environmentally persistent free radicals decrease cardiac function and increase pulmonary artery pressure

“…In separate studies, left ventricular (LV) function was also significantly decreased when isolated hearts from SHRs and normotensive rats were directly perfused with DEP (43,44). Our group (27) showed that a large, single intratracheal instillation of EPFRs decreased LV function and exacerbated the decreases in LV function produced in response to a brief period of ischemia and reperfusion. While particle administration can affect cardiac function in "at risk" animals or exacerbate the functional deficits and damage produced by cardiac ischemia, the question of whether exposure to airborne PM, in particular EPFRs, can alter baseline ventricular function in otherwise healthy rats has not been studied.…”

“…While the biological actions of EPFRs are only starting to be studied, evidence suggests that PM with intrinsic redox potential may have enhanced biological activity beyond that of the particle itself (4,5,16,27). Inhalation of EPFRs has been shown to produce pulmonary toxicity in neonatal rats (5,27). Diesel exhaust particles (DEPs) containing redox active species also produce endothelial damage and exacerbate atherosclerotic disease in mice (1).…”

“…These EPFRs persist in the air for days or weeks and, upon redox cycling, produce a sustained release of ROS (26). While the biological actions of EPFRs are only starting to be studied, evidence suggests that PM with intrinsic redox potential may have enhanced biological activity beyond that of the particle itself (4,5,16,27). Inhalation of EPFRs has been shown to produce pulmonary toxicity in neonatal rats (5, 27).…”