Role of the cyclic AMP-dependent pathway in free radical-induced cholesterol accumulation in vascular smooth muscle cells

We have previously reported that free radical-treated vascular smooth muscl e cells (SMC) lead to cholesterol accumulation in vitro. In the current stu dy, we investigated the effects of oxidative stress on cyclic AMP concentra tion and cAMP-dependent enzymes involved in cholesterol homeostasis in A7r5 cells. Under our conditions of a mild oxidative stress, namely with no cha nge in cell viability, we found that free radicals, initiated using azobis- amidino-propane dihydrochloride (AAPH), resulted in a dose-dependent decrea se in cellular cAMP which was opposed by vitamin E preincubation. Although the addition of adenylate cyclase activators (carbacyclin and forskolin) in creased cAMP levels it did not succeed in restoring the AAPH-induced decrea se. The oxidative stress-induced increase in activities of 3-hydroxy-3-meth ylglutaryl coenzyme A reductase and of acyl coenzyme A: cholesterol acyltra nsferase and the decrease in neutral cholesteryl ester hydrolase activity w ere suppressed by addition of dibutyryl cAMP. Taken together, these results strongly suggest that free radicals reduce cAMP concentrations by altering cell membrane adenylate cyclase activity. The changes of cAMP-dependent en zymes induced by oxidative stress resulting in cholesterol accumulation mig ht be one of the processes leading to SMC-derived foam cells depicted in at heroma plaque. Moreover, if extrapolated to in vivo, these data may explain in part the beneficial effects of antioxidants in the reduction of cardiov ascular diseases. (C) 2000 Elsevier Science Inc.