Advanced glycation endproducts induce a proliferative response in vascular smooth muscle cells via altered calcium signaling.
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 (Ca2+) 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 Ca2+ increase, although not increased in amplitude, was significantly prolonged in cells preincubated with glycated albumin. Intracellular Ca2+ imaging and electrophysiological recording of ion channel currents following release of caged Ca2+ indicated that this prolonged Ca2+ rise occurred predominantly via changes in Ca2+-induced Ca2+ 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 Ca2+ rise following preincubation with glycated albumin, the S1P-induced activation of the Ca2+-dependent phosphatase, calcineurin (CaN) was increased. This resulted in increased S1P-induced activation of the Ca2+-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 Ca2+ increase leading to increased activation of CaN and subsequently NFATc. This mechanism may contribute to pathogenesis of vascular disease in diabetes mellitus.
David
Kanola C
KC
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.
Scott
Roderick H
RH
Nixon
Graeme F
GF
D000818:Animals; D002118:Calcium / Q000819:agonists / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D013552:Swine; D015854:Up-Regulation / Q000502:physiology
D017127:Glycation End Products, Advanced; D002118:Calcium