Abstract-Three 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HCRIs), atorvastatin, pravastatin, and cerivastatin, inhibited phorbol ester-stimulated superoxide anion (O 2 Ϫ ) formation in endothelium-intact segments of the rat aorta in a time-and concentration-dependent manner (maximum inhibition of 70% after 18 hours at 1 to 10 mol/L). The HMG-CoA reductase product mevalonic acid (400 mol/L) reversed the inhibitory effect of the HCRIs, which, conversely, was mimicked by inactivation of p21 Rac with Clostridium sordellii lethal toxin but not by inactivation of p21 Rho with Clostridium botulinum exoenzyme (C3). A mevalonate-sensitive inhibition of phorbol ester-stimulated O 2 Ϫ formation by atorvastatin was also observed in porcine cultured endothelial cells and in a murine macrophage cell line. In the rat aorta, no effect of the HCRIs on protein kinase C, NADPH oxidase, or superoxide dismutase (SOD) activity and expression was detected, whereas that of endothelial nitric oxide (NO) synthase was enhanced Ϸ2-fold. Moreover, exposure of the segments to atorvastatin resulted in a significant improvement of endothelium-dependent NO-mediated relaxation, and this effect was abolished in the presence of SOD. Taken together, these findings suggest that in addition to augmenting endothelial NO synthesis, HCRIs inhibit endothelial O 2 Ϫ formation by preventing the isoprenylation of p21 Rac, which is critical for the assembly of NADPH oxidase after activation of protein kinase C. The resulting shift in the balance between NO and O 2 Ϫ in the endothelium improves endothelial function even in healthy blood vessels and therefore may provide a reasonable explanation for the beneficial effects of HCRIs in patients with coronary heart disease in addition to or as an alternative to the reduction in serum LDL cholesterol. Key Words: HMG-CoA reductase inhibitor(s) Ⅲ endothelial dysfunction Ⅲ coronary heart disease Ⅲ nitric oxide Ⅲ superoxide anion Ⅲ NADPH oxidase Ⅲ p21 Rac T he beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HCRIs), collectively referred to as "statins," on coronary events have generally been attributed to the well-documented LDL cholesterol-lowering properties of these drugs. However, despite the strong association between drug concentration, blood lipid level, and patient benefit shown in the CARE, 4S, and WOSCOPS trials, HCRIs seem to exert at least part of their cardioprotective action by mechanisms other than simply lowering the lipid load of the vessel wall. Thus, HCRIs induce regression of atherosclerotic lesions in patients with coronary heart disease (CHD) with and without hypercholesterolemia 1 and improve endothelial dysfunction, a hallmark of atherosclerotic blood vessels, in patients with moderately elevated total serum cholesterol within 1 month. 2 At the cellular level, they modulate leukocyte activity and adhesiveness, 3,4 inhibit vascular smooth muscle cell proliferation both in vitro and in vivo, 5,6 and reduce the synthesis of che...
The enigma why the mycotoxin ochratoxin A (OTA) impairs cell and organ function is still not solved. However, an interaction with target molecules is a prerequisite for any observed adverse effect. This interaction depends on characteristics of the target molecule as well as on the OTA molecule itself. OTA has different structural moieties which may be relevant for these interrelations including a halogen (chlorine) and an amino acid group (phenylalanine). To test their importance for the impact of OTA, detailed structure-activity studies with various OTA derivatives were performed. For this, 23 OTA derivatives were available, which were modified by either an exchange of the halogen moiety against another halogen (fluorine, iodine or bromine) or by the amino acid moiety against another one (tyrosine or alanine) or a combination of both. Additionally, the configuration of the 3R carbon atom was changed to 3S. These derivatives were tested in human renal cells for their ability to induce cell death (cytotoxicity, apoptosis, necrosis), their impact on collagen protein secretion and for their influence on gene expression. It turned out that the substitution of the amino acid moiety against tyrosine or alanine almost completely prevented the adverse effects of OTA. The exchange of the halogen moiety had minor effects and the inversion of the stereochemistry at C3 did not prevent the effects of OTA. Therefore, we conclude that the amino acid moiety of OTA is indispensable for the interaction of OTA with its target molecules.
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