Dalcetrapib
JTT-705 blocks vascular smooth muscle cell proliferation and angiogenesis through a mechanism independent of CETP inhibition (Atherosclerosis 2005)
Original title: JTT-705 blocks cell proliferation and angiogenesis through p38 kinase/p27(kip1) and Ras/p21(waf1) pathways
Because excessive proliferation and migration of vascular smooth muscle cells (SMCs) contributes to atherosclerotic plaque growth and instability, researchers examined whether the CETP inhibitor JTT-705 acts directly on SMCs and endothelial cells (ECs). JTT-705 inhibited human coronary artery SMC proliferation, inducing phosphorylation of p38 MAPK and ERK, with the antiproliferative effect blocked by a p38 MAPK inhibitor. JTT-705 also upregulated p21(waf1), an effect blocked by dominant-negative Ras but not by p38 MAPK or ERK inhibitors, and upregulated p27(kip1) through a p38 MAPK-dependent pathway. Culture medium from JTT-705-treated SMCs blocked coronary artery EC tube formation in an angiogenesis model, both indirectly through reduced VEGF from SMCs and directly through an antiproliferative effect on ECs, indicating that JTT-705 has a direct anti-atherogenic action beyond its effect on CETP activity.
Original abstract
The excessive proliferation and migration of vascular smooth muscle cells (SMCs) participate in the growth and instability of atherosclerotic plaque. We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein, JTT-705, on SMC proliferation and angiogenesis in endothelial cells (ECs). JTT-705 inhibited human coronary artery SMC proliferation. JTT-705 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinases (ERK) in SMCs. In addition, the anti-proliferative effects of JTT-705 in SMCs were blocked by p38 MAPK inhibitor. JTT-705 induced the upregulation of p-p21(waf1), and this effect was blocked by dominant-negative Ras (N17), but not by inhibitors of p38 MAPK or ERK. In addition, JTT-705 also induced the upregulation of p27(kip1), and this effect was blocked by p38 MAPK inhibitor. Interestingly, culture medium from JTT-705-treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor (VEGF) from SMCs and directly via an anti-proliferative effect in ECs. JTT-705 blocked the proliferation of SMCs through the activation of p38 kinase/p27(kip1) and Ras/p21(waf1) pathways, and simultaneously blocked EC tube formation associated with a decrease in VEGF production from SMCs and an anti-proliferative effect in ECs. Our results indicate that JTT-705 may induce a direct anti-atherogenic effect in addition to its inhibitory effect of CETP activity.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.