Increased radiosensitivity and radioresistant DNA synthesis in cultured fibroblasts from patients with coronary atherosclerosis

Abstract

Cultured skin fibroblasts from five patients with atherosclerosis who underwent coronary artery bypass graft surgery were compared with those from one ataxia telangiectasia (AT) homozygote, three AT heterozygotes, and five healthy subjects to determine their sensitivity to gamma radiation as determined by a colony survival assay. Fibroblasts from four of these patients were also compared with those from two AT homozygotes, two AT heterozygotes, and three healthy subjects to determine postirradiation [3H]thymidine incorporation, indicating the levels of radioresistant DNA synthesis (RDS). On the basis of colony survival assay, after long-term irradiation (at low dose rate, ie, 0.007 Gy/min), fibroblasts from all five patients with atherosclerosis exhibited radiosensitivity that was intermediate between that of the healthy subjects and that of patients with the known radiosensitive syndrome AT. However, there was a considerable interstrain difference in the radiosensitivity of fibroblasts from patients with atherosclerosis, with their mean D10 values (radiation dose resulting in 10% cell survival) varying between 2.3 and 6.2 Gy, whereas the mean D10 values for the cells from the AT homozygote, AT heterozygotes, and healthy subjects were 2.0,3.8, and 9.0 Gy, respectively. One of the patients with atherosclerosis showed cellular radiosensitivity quite similar to that of the AT homozygote, up to 2% to 10% of survival levels after short- (at a dose rate of 8 Gy/min) and long-term irradiation, respectively. The results of [3H]thymidine incorporation showed an AT heterozygote-Iike RDS in fibroblasts from patients with atherosclerosis that appeared to be intermediate between that of AT homozygotes and that of healthy subjects, suggesting a partial deregulation of cell cycle in the patients with atherosclerosis. Overall, the results suggest that increased cellular radiosensitivity and/or altered cell cycle regulation may be associated with atherosclerosis.