O34	Early coronary atherogenesis as a consequence of chronic in-vivo proteasome inhibition.
J.Herrmann, A.Saguner, M.Olson, L.Lerman, A.Lerman
Mayo Clinic Rochester, Rochester, US.

Background: Proteasome inhibitors (PSI) are an emerging class of drugs in cancer therapy; however, their cardiovascular effects with chronic use remain less well defined, which was the objective of the current study. Methods and Results: Female pigs, 3 months of age, remained untreated (N, n=4) or were treated with twice weekly SQ injections of the boronate-type PSI MLN-273 (0.08 mg/kg, N+PSI, n=4) or received a hypercholesterolemic diet (2% cholesterol, 15% lard, HC, n=4) for a period of 12 weeks. Coronary vasorelaxation was assessed by organ chamber experiments with increasing concentrations of bradykinin (BK, log -10.5 to -6.5 M) and sodium nitroprusside (SNP, log -9 to -5 M), coronary artery intima-media ratio by morphometric analysis on elastica-van-Gieson-stained slides, coronary artery vasa vasorum density by 3D micro-CT, and coronary artery expression of the p47 phox (NOXO1) regulatory subunit of NAD(P)H oxidase by immunoblotting. Results are as listed in Table 1. Table 1 mean ± SEM N HC N+PSI Vasorelaxation to BK 10-6.5 M [%] 90.6±2.1* 69.7± 6.7* 49.9±6.3 Vasorelaxation to SNP 10-5 M [%] 56.1±7.4 66.0±5.9 68.8±7 Intima-media ratio 0.025 ±0.004** 0.073 ±0.025 0.090 ±0.039 Vasa vasorum density [n/mm2] 2.91± 0.26* 5.10±0.37 4.75±0.45 p47 phox/beta-actin densitometric ratio 0.446 ±0.68* 0.694 ±0.25 0.769 ±0.096     * p≤0.05 vs. other groups ** p=0.01 vs. other groups Conclusion: Chronic proteasome inhibition is associated with functional and structural coronary artery alterations as they can be seen with coronary risk factor exposure and potentially relate to increase in oxidative stress as the common pathway.

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