() Mechanism of Acrolein-induced Vascular Toxicity.
Yousefipour, Z1, Ranganna, K1, Newaz, M1, Milton, M1, 1 Txas Southern University, Houston, TX, USA
ABSTRACT- Acrolein-a major component of cigarette smoke, an environmental pollutant and a lipid peroxidation product, is implicated in vascular pathogenesis. The purpose of the present study is to investigate the direct effects of acrolein on vascular function and to understand the mechanism underlying the toxicity. The present study hypothesizes that acrolein alters normal function and responses of blood vessels by changing the redox state of the vasculature. Male Sprague-Dawley rats (n=4) were treated with 4 mg/kg of acrolein (i.p.) daily for 7 days. Blood pressure was determined by tail-cuff plethysmography. Vascular responsiveness was assessed by investigating the effect of acrolein treatment on vascular response elicited by phenylephrine (PE) (10-9 to 10-5) and acetylcholine (Ach)(10-8 to 10-5) in isolated rat aortic ring prepration. Acrolein treatment not only increased systolic blood pressure by 25% (p<0.05) but also increased vasoconstriction response to phenylephrine (PE) by about 100%. The role of NO in acrolein-induced changes in vasoconstriction response to PE was determined by measuring nitrite content in urine samples using Greiss reaction and cGMP levels in plasma by enzyme-immuno assay (EIA). Alteration in antioxidant status was determined by measuring glutathione peroxidase(GSH-Px) and glutathione S-transferase (GST)activity in tissue homogenates. Treatment of rats with acrolein resulted in about 23% (p<0.05) and 90% (p<0.05) reduction in urinary nitrite excretion and plasma cGMP levels, respectively. On the other hand, GSH-Px and GST activity in aortic tissue was increased by about 5 and 1.2 fold(p<0.05) in response to acrolein treatment respectively. Western blot analysis of GST protein revealed a 2 fold induction. Measurement of lipid peroxidation products (LPOs)in tissue homogenates was used for assessment of generation of reactive oxygen species and indicated a 120% increased. These results suggest that acrolein-induced increased vascular contractility is potentially due to reduction in production and /or bioavailability of NO, via a redox sensitive mechanism, and impairment of antioxidant defense system. [Supported by G12RR03045, NCRR, NIH and the resources from Center for Cardiovascular Diseases, Texas Southern University]
Key words: antioxidant, acrolein, redox state