Marginal dietary zinc deficiency in vivo induces vascular smoothmuscle cell apoptosis in large arteries

Abstract

Aims Dietary zinc deficiency has been associated with the development of atherosclerosis although the effects on vascular smooth muscle cells (VSMCs), important in maintaining atherosclerotic plaque integrity, are unknown. The main aim of this study was to elucidate the effect of a zinc-deficient environment on VSMCs using an in vivo model. Methods and results Ratswere maintained for 2weeks on a marginally zinc-deficient diet which resulted in a significant reduction in plasma zinc levels. Large arteries from zinc-deficient rats had significantly increased apoptosis within theVSMClayers compared with arteries from rats on a zinc-adequate diet. This apoptosis occurred in parallel with a known apoptotic pathway, namely dephosphorylation of the pro-apoptotic protein Bcl-2-associated deathpromoter protein (BAD). Activation of extracellular signal-regulated kinase (ERK)1/2, which maintains BAD phosphorylation as a pro-survival mechanism, was decreased in arteries from zinc-deficient rats. The mechanisms of this in vivo effect were investigated in vitro. Cultured rat VSMCs incubated with plasma from zinc-deficient rats similarly resulted in increased apoptosis in parallel with BAD dephosphorylation and decreased ERK1/2 activation. Further related apoptotic mechanisms induced by plasma from zinc-deficient rats involved a prolonged rise in [Ca2+]i leading to subsequent activation of the phosphatase calcineurin. Calcineurin activationwas required to dephosphorylate BAD. In addition, an increase in oxidative stress contributed to the apoptotic effect induced by plasma from zinc-deficient rats. Conclusion In conclusion, a marginally zinc-deficient diet is pro-apoptotic for VSMCs and this may contribute to cardiovascular disease.