Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.
Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.
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DOI：
10.1161/atvbaha.112.300234
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Wu JH;Fanaroff AC;Sharma KC;Smith LS;Brian L;Eipper BA;Mains RE;Freedman NJ;Zhang L
Kalirin is a multifunctional protein that contains two guanine nucleotide exchange factor (GEF) domains for the GTPases Rac1 and RhoA. Variants of KALRN have been associated with atherosclerosis in humans, but Kalirin’s activity has been characterized almost exclusively in the CNS. We therefore tested the hypothesis that Kalirin functions as a RhoGEF in arterial smooth muscle cells (SMCs). Kalirin-9 protein is expressed abundantly in aorta and bone marrow, as well as in cultured SMCs, endothelial cells, and macrophages. Moreover, arterial Kalirin was up-regulated during early atherogenesis in apolipoprotein E-deficient mice. In cultured SMCs, signaling was affected similarly in three models of Kalirin loss-of-function: heterozygous Kalrn deletion, Kalirin RNAi, and treatment with the Kalirin RhoGEF-1 inhibitor 1-(3-nitrophenyl)-1H-pyrrole-2,5-dione. With reduced Kalirin function, SMCs showed normal RhoA activation but diminished Rac1 activation, assessed as reduced Rac-GTP levels, p21-activated kinase autophosphorylation, and SMC migration. Kalrn−/+ SMCs proliferated 30% less rapidly than WT SMCs. Neointimal hyperplasia engendered by carotid endothelial denudation was ~60% less in Kalrn−/+ and SMC-specific Kalrn−/+ mice than in control mice. Kalirin functions as a GEF for Rac1 in SMCs, and promotes SMC migration and proliferation both in vitro and in vivo.
