REJUVENATION RESEARCH Volume 11, Number 2, 2008 © Mary Ann Liebert, Inc. DOI: 10.1089/rej.2008.0665 Modulation of Genes Involved in Zinc Homeostasis in Old Low-Grade Atherosclerotic Patients Under Effects of HMG-CoA Reductase Inhibitors Laura Costarelli, 1 Elisa Muti, 1 Marco Malavolta, 1 Robertina Giacconi, 1 Catia Cipriano, 1 Davide Sartini, 2 Monica Emanuelli, 2 Mauro Silvestrini, 3 Leandro Provinciali, 3 Beatrice Gobbi, 3 and Eugenio Mocchegiani 1 ABSTRACT Taking into account the antioxidant properties of zinc, it is difficult to explain the beneficial effects of HMG-CoA reductase inhibitors in the context of a well-known decreased zinc sta- tus. Therefore, intracellular zinc homeostasis was studied in patients with low-grade carotid atherosclerosis under treatment with HMG-CoA reductase inhibitors using a custom mi- croarray-based approach developed by pooling information across microarray studies. Ex- perimental data unravel an active zinc signaling in PBMC from low-grade atherosclerotic pa- tients under lipid reduction therapy, suggesting that monitoring intracellular zinc status could be a key factor for an optimal strategy and targeting a level of intervention. 287 INTRODUCTION S EVERAL STUDIES have indicated that zinc has an antioxidant and antiatherosclerotic ef- fect. Early atherosclerotic lesion formation is accelerated by free radical production, and in- tracellular zinc signals might antagonize such effects through a selective modulation of tran- scription factors involved in the antioxidant re- sponse. Moreover, abnormal zinc and lipid plasma levels occur more frequently in athero- sclerotic patients, 1 perhaps due to the involve- ment of zinc-dependent enzymes in cholesterol and triacylglycerols synthesis. 2 Commonly, these lipid alterations include increase in triglyceride and LDL-cholesterol plasma levels, which in turn are key factors in the emergence of cardiovascular complications. The impor- tance of the treatment of dyslipidemia with the widely used HMG-CoA reductase inhibitors became evident with the increased life ex- pectancy and reports of reduced risk for major cardiovascular events. 3 However, HMG-CoA reductase inhibitor treatment induces a reduc- tion in mean serum zinc generally associated with significant antioxidant properties. 4,5 Tak- ing into account the well-described antioxidant properties of zinc, it is difficult to explain the beneficial effects of HMG-CoA reductase in- hibitors in the context of a possible decrease of zinc status. However, it is well known that plasma zinc does not always represent a good marker of zinc status, 6,7 and it is also true that an effective method for measuring zinc status is still lacking. By contrast, the gene pathways modulated in the presence/absence of zinc 1 Immunology Center, Section of Nutrition, Immunity and Ageing, Research Department, INRCA, Ancona, Italy. 2 Biochemistry and Biotechnology Institute, Università Politecnica delle Marche, Ancona, Italy. 3 Neurological Clinic, Università Politecnica delle Marche, Torrette Hospital, Ancona, Italy.