Target For Proliferative Vascular Diseases Research Articles

Lipopolysaccharide induced vascular smooth muscle cells proliferation: A new potential therapeutic target for proliferative vascular diseases.

Vascular smooth muscle cells (VSMCs) proliferation is involved in vascular atherosclerosis and restenosis. Recent studies have demonstrated that lipopolysaccharide (LPS) promotes VSMCs proliferation, but the signalling pathways which are involved are not completely understood. The purpose of this review was to summarize the existing knowledge of the role and molecular mechanisms involved in controlling VSMCs proliferation stimulated by LPS and mediated by toll-like receptor 4 (TLR4) signalling pathways. Moreover, the potential inhibitors of TLR4 signalling for VSMCs proliferation in proliferative vascular diseases are discussed.

CREG mediated adventitial fibroblast phenotype modulation: A possible therapeutic target for proliferative vascular disease

Proliferative vascular diseases, of which neointimal formation is a key pathological feature, cause significant morbidity and mortality worldwide. Adventitia is the outermost connective tissue that surrounds an artery. In recent years, accumulating data indicate that adventitial fibroblasts participate in the formation of neointimal lesions. Our previous studies have demonstrated that cellular repressor of E1A-stimulated genes (CREG) plays critical roles in reducing neointimal hyperplasia by promoting vascular smooth muscle cell (VSMC) differentiation and grow arrest and inhibiting migration. Hence, it is plausible that genetical modification with CREG gene in adventitial fibroblasts might inhibit angiotensin II-induced transdifferentiation to myofibroblasts, proliferation and migration, as well as adventitial thickening, finally decreasing neointimal formation. Possible mechanisms may include CREG direct attenuation of reactive oxygen species derived from reduced cathepsin-dependent activation of NADPH oxidase and indirect suppression of the downstream of NADPH oxidase including ERK1/2, JNK and p38 MAPK pathways in adventitial fibroblasts. Therefore, CREG may be a potential therapeutic target for proliferative vascular diseases.

Caldesmon as a Therapeutic Target for Proliferative Vascular Diseases

Caldesmon is a negative regulator of cell proliferation, migration, and metalloproteinase release. Caldesmon function is regulated by multiple kinases, targeting multiple phosphorylation sites. Recently, overexpression of caldesmon has been shown to inhibit neointimal formation after experimental angioplasty, suggesting that caldesmon may be a potential therapeutic target for proliferative vascular diseases.

Atorvastatin inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to inhibit vascular smooth muscle cell growth, a key event in the pathogenesis of proliferative vascular diseases. The mechanism by which HMG-CoA reductase inhibitors exert their antiproliferative activity is not fully understood, especially their effect on DNA replication. We therefore investigated the effects of atorvastatin on minichromosome maintenance (MCM) protein 6 and 7 expression in vascular smooth muscle cells, two proteins essential for initiation of DNA replication. Stimulation of quiescent rat aortic vascular smooth muscle cells with fetal bovine serum induced MCM6 and MCM7 protein and mRNA expression, which was potently attenuated by atorvastatin in a dose-dependent fashion. Mevalonate completely abrogated the inhibitory effect on serum-induced MCM6 and MCM7 expression, demonstrating that biosynthesis of isoprenoids was likely the specific pathway blocked by atorvastatin. Transient transfection experiments revealed that atorvastatin inhibited MCM6 and MCM7 promoter activity, implicating a transcriptional mechanism. The MCM6 and MCM7 promoters contain several E2F sites critical for their transcriptional activation. Activity of a luciferase reporter plasmid containing four E2F elements was also strongly inhibited by atorvastatin. The inhibitory effect of atorvastatin on MCM6 and MCM7 was reversed by adenoviral-mediated overexpression of E2F, indicating that their downregulation by atorvastatin involves an E2F-dependent mechanism. These findings demonstrate that MCM proteins play an essential role during the proliferation of vascular smooth muscle cells and may provide a novel therapeutic target for proliferative vascular diseases. Inhibition of MCM6 and MCM7 expression by blocking E2F function may contribute importantly to the inhibition of vascular smooth muscle cell DNA synthesis by atorvastatin.

Retinoid Ligands Inhibit Cell Proliferation by Modulating Cell Cycle Regulators in Human Coronary Smooth Muscle Cells

P74 Retinoids inhibit vascular smooth muscle cell proliferation in vitro and intimal hyperplasia in vivo in rats. We examined the underlying mechanism of the antiproliferative effect of retinoids on human coronary smooth muscle cells (CASMC). The retinoids tested included: RAR ligands, all-trans retinoic acid (atRA) and Ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-propenyl]-benzoic acid (TTNPB); a RXR and RAR ligand 9-cis retinoic acid (9cRA); and the potent RXRα- ligand AGN4204. All retinoids inhibited DNA synthesis in CASMC stimulated with platelet derived growth factor and insulin (IC 50 : TTNPB 0.063μM, atRA 0.123μM, AGN4204 0.461μM, 9cRA 1.529μM, all p<0.01, n=6). All retinoids substantially attenuated retinoblastoma protein phosphorylation which is required for CASMC proliferation (maximal inhibition: TTNPB and atRA, 2x10 -7 M; AGN4204 and 9cRA, 2x10 -6 M all p<0.01, n=3). None of the retinoids affected the expression of CDKs 2, 4, or 6 or cyclin E. TTNPB, atRA and AGN4204 inhibited the mitogenic induction of cyclin D1 (maximal inhibition: TTNPB, 2x10 -9 M; atRA, 2x10 -7 M; AGN4204, 2x10 -6 M, all p<0.01, n=3), whereas 9cRA had no effect (n=3). All retinoids significantly attenuated mitogen-induced downregulation of CDKI p27 Kip1 , a major negative regulator of G1 cyclin/CDK activity (maximal effect: TTNPB and atRA, 2x10 -7 M; AGN4204 and 9cRA, 2x10 -6 M, all p<0.01, n=3). The present study demonstrate that retinoids have antiproliferative activity by modulating the G1→S cell cycle regulators in human CASMC, which may provide a novel therapeutic target for proliferative vascular diseases.