Advanced glycation endproducts induce a proliferative response in vascular smooth muscle cells via altered calcium signaling

Abstract

Advanced glycation endproducts (AGEs) are proteins that accumulate in the plasma of diabetics as a result of increased glucose concentrations and are closely linked with vascular disease. The mechanisms involved are still not clear. The aim of this study was to investigate whether AGE-induced changes in calcium (Ca 2+) homeostasis could contribute to these mechanisms. Cultured porcine coronary artery vascular smooth muscle (VSM) cells were preincubated with glycated albumin for 96 h. The sphingosine 1-phosphate (S1P)-induced intracellular Ca 2+ increase, although not increased in amplitude, was significantly prolonged in cells preincubated with glycated albumin. Intracellular Ca 2+ imaging and electrophysiological recording of ion channel currents following release of caged Ca 2+ indicated that this prolonged Ca 2+ rise occurred predominantly via changes in Ca 2+-induced Ca 2+ release. Preincubation with glycated albumin also resulted in a threefold increase in expression of the receptor for AGE. As a consequence of the prolonged intracellular Ca 2+ rise following preincubation with glycated albumin, the S1P-induced activation of the Ca 2+-dependent phosphatase, calcineurin (CaN) was increased. This resulted in increased S1P-induced activation of the Ca 2+-dependent transcription factor, nuclear factor of activated T cells (NFATc). BrdU incorporation in VSM cells was increased in cells preincubated with glycated albumin and was inhibited by the CaN inhibitor, cyclosporin A. In conclusion, AGE can induce VSM proliferation via a prolonged agonist-induced Ca 2+ increase leading to increased activation of CaN and subsequently NFATc. This mechanism may contribute to pathogenesis of vascular disease in diabetes mellitus.