Receptor interacting protein 3 suppresses vascular smooth muscle cell growth by inhibition of the phosphoinositide 3-kinase-Akt axis.
Proliferation of vascular smooth muscle cells (VSMCs) is a primary mechanism underlying cardiovascular proliferative disorders. Phosphoinositide 3-kinase (PI3K)-Akt (or protein kinase B) axis has been assigned at the center of pathways that regulate cell proliferation. Here we demonstrate that enhanced PI3K-Akt signaling by mitogenic stimulation or arterial injury profoundly elevates expression of receptor interacting protein 3 (RIP3) in primary cultured rat VSMCs and in vivo and that the up-regulation of RIP3 leads to VSMC growth arrest and apoptosis via inhibiting the PI3K-Akt signaling pathway, thereby alleviating balloon injury-induced neointimal formation. Specifically, mitogenic stimulation with platelet-derived growth factor-BB or angiotensin II leads to a profound increase in RIP3 expression, which is abolished by inhibition of PI3K or Akt, and increased PI3K-Akt signaling by expression of a constitutively active PI3K mutant also elevates RIP3 expression. Importantly, adenoviral overexpression of RIP3 not only triggers apoptosis but also causes cell cycle arrest at G(1)/G(0) phases that is associated with suppressed Akt activation. In sharp contrast, RIP3 gene silencing enhances serum- and platelet-derived growth factor-induced cell proliferation and Akt activation. In vivo adenoviral gene delivery of rat RIP3 (rRIP3) increased apoptosis and reduced VSMC proliferation, thus, effectively alleviating balloon injury-induced neointimal formation. The growth-suppressive and pro-apoptotic effects are independent of rRIP3 Ser/Thr kinase activity, because overexpression of a kinase-inactive mutant of rRIP3, similar to its wild type, is sufficient to induce growth arrest and apoptosis. These findings reveal a novel growth-suppressive action of RIP3, marking RIP3 as an important factor to prevent excessive mitogenic stimulation- or injury-induced vascular smooth muscle cells hyperplasia.
Li
Qian
Q
Institute of Cardiovascular Sciences, Peking University, 100083 Beijing; Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Li
Geng
G
Institute of Cardiovascular Sciences, Peking University, 100083 Beijing.
Lan
Xiaomei
X
Institute of Cardiovascular Sciences, Peking University, 100083 Beijing; Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Zheng
Ming
M
Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Chen
Kuang-Hueih
KH
Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Cao
Chun-Mei
CM
Institute of Molecular Medicine, Peking University, 100871 Beijing, China. Electronic address: Caochunmei@pku.edu.cn.
Xiao
Rui-Ping
RP
Institute of Cardiovascular Sciences, Peking University, 100083 Beijing; Institute of Molecular Medicine, Peking University, 100871 Beijing, China; Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224. Electronic address: Xiaor@grc.nia.nih.gov.
D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000378:metabolism; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D011921:Rats, Inbred WKY; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053422:Receptor-Interacting Protein Serine-Threonine Kinases