Calcium homeostasis in vascular smooth muscle cells is altered in type 2 diabetes by Bcl-2 protein modulation of InsP3R calcium release channels

Velmurugan GV, White C. Calcium homeostasis in vascular smooth muscle cells is altered in type 2 diabetes by Bcl-2 protein modulation of InsP(3)R calcium release channels. Am J Physiol Heart Circ Physiol 302: H124-H134, 2012. First published October 28, 2011; doi:10.1152/ajpheart.00218.2011.-This study examines the extent to which the antiapoptotic Bcl-2 proteins Bcl-2 and Bcl-X-L contribute to diabetic Ca2+ dysregulation and vessel contractility in vascular smooth muscle cells (VSMCs) through their interaction with inositol 1,4,5-trisphosphate receptor (InsP(3)R) intracellular Ca2+ release channels. Measurements of intracellular ([Ca2+](i)) and sarcoplasmic reticulum ([Ca2+](SR)) calcium concentrations were made in primary cells isolated from diabetic (db/db) and nondiabetic (db/m) mice. In addition, [Ca2+](i) and constriction were recorded simultaneously in isolated intact arteries. Protein expression levels of Bcl-X-L but not Bcl-2 were elevated in VSMCs isolated from db/db compared with db/m age-matched controls. In single cells, InsP(3)-evoked [Ca2+](i) signaling was enhanced in VSMCs from db/db mice compared with db/m. This was attributed to alterations in the intrinsic properties of the InsP(3)R itself because there were no differences between db/db and db/m in the steady-state [Ca2+](SR) or InsP(3)R expression levels. Moreover, in permeabilized cells the rate of InsP(3)R-dependent SR Ca2+ release was increased in db/db compared with db/m VSMCs. The enhanced InsP(3)-dependent SR Ca2+ release was attenuated by the Bcl-2 protein inhibitor ABT-737 only in diabetic cells. Application of ABT-737 similarly attenuated enhanced agonist-induced [Ca2+](i) signaling only in intact aortic and mesenteric db/db vessels. In contrast, ABT-737 had no effect on agonist-evoked contractility in either db/db or db/m vessels. Taken together, the data suggest that in type 2 diabetes the mechanism for [Ca2+](i) dysregulation in VSMCs involves Bcl-2 protein-dependent increases in InsP(3)R excitability and that dysregulated [Ca2+](i) signaling does not appear to contribute to increased vessel reactivity.