Increased SMC proliferation after endothelial injury in hyperinsulinemic obese Zucker rats

The long-term effect of long-lasting hyperinsulinemia on aortic smooth muscle cell (SMC) proliferation after endothelial injury was investigated using the obese Zucker rat model, which is characterized especially by early spontaneous development of hyperinsulinemia and insulin resistance. SMC proliferation was provoked by the passage of an embolectomy catheter with a tightly inflated balloon and was assessed by measuring the incorporation of [3H]thymidine in the DNA of intima-media layers. Compared with controls, the SMC mitotic activity was not significantly increased from day 2 to day 7 after injury, but from day 14 to day 30 after endothelial denudation, SMC proliferation was significantly less decreased in obese than in lean rats [on day 14, DNA synthesis = 107 +/- 18 counts min-1 microgram DNA-1 in lean and 345 +/- 44 counts min-1.microgram DNA-1 in obese rats (P = 0.003); and on day 30 DNA synthesis = 74 +/- 18 counts min-1.microgram DNA-1 in lean and 133 +/- 19 counts min-1 microgram DNA-1 in obese rats (P = 0.0055)]. As a result, the intima-media DNA content was higher in obese than in lean rats on day 14 and even more so on day 30, suggesting a higher amount of SMCs in the intima-media. Moreover, on day 30, the aortic thickening, as measured by a histomorphometric technique, was much higher in obese than in lean rats. This difference was entirely due to an increase in SMC content of the intima, mainly resulting from a dramatic increment in the number of nuclei and nuclear number density. Then long-lasting and chronic hyperinsulinemia may play an important role in SMC proliferation after endothelial denudation, which in turn can contribute to intimal thickness. The usefulness of the obese Zucker rat model is discussed.