Address for correspondence: Lawrence Hightower, Ph.D., Department of Molecular and Cell Biology, University of Connecticut, 91 N. Eagleville Rd., Storrs, Connecticut. 06269 USA Phone: +1-860-486-4257; FAX: +1-860-486-4331 e-mail: lawrence.hightower@uconn.edu Heavy metal ions in normal physiology, toxic stress and cytoprotection MICHAEL A. LYNES a , Y. JAMES KANG b , STEFANO L. SENSI c , GEORGE A. PERDRIZET d , AND LAWRENCE E. HIGHTOWER a a University of Connecticut, Storrs, CT 06269 USA,; b University of Louisville, Louisville, KY 40202 USA; c University’G. d’Annunizio’, Chieti 66013 ITALY; d Hartford Hospital, Hartford, CT 06169 USA ABSTRACT: As a group, heavy metals include both those essential for normal biological functioning (e.g. Cu and Zn), and non-essential metals (e.g. Cd, Hg, and Pb). Both essential and non-essential metals can be present at concentrations that disturb normal biological functions, and which evoke cellular stress responses. The cellular targets for metal toxicity include tissues of the kidney, liver, heart, immune response and nervous system. Intriguingly, manipulations of specific metals, their reservoirs, and the cellular stress response can have therapeutic effects on certain diseases. In this minireview, we will consider both the biological responses to stressful levels of heavy metal cations, and experimental and clinical manipulations of these cations as a means to improve human health parameters. KEYWORDS: heavy metal, zinc, cadmium, tin, copper, cardiomyopathy, chelation, ischemia, inflammation, cytoprotection, heme-oxygenase, heat shock proteins, vascular surgery, immunomodulation, metallothionein, humoral immunity, neuronal injury, oxidative stress INTRODUCTION Heavy metals represent both essential components for the maintenance of normal biological functions, and toxic agents with damaging consequences when present in inappropriate amounts. One way to understand these agents as a group is