The cell cycle: a critical therapeutic target to prevent vascular proliferative disease

Abstract

Percutaneous coronary intervention is the preferred revascularization approach for most patients with coronary artery disease. However, this strategy is limited by renarrowing of the vessel by neointimal hyperplasia within the stent lumen (in-stent restenosis). Vascular smooth muscle cell proliferation is a major component in this healing process. This process is mediated by multiple cytokines and growth factors, which share a common pathway in inducing cell proliferation: the cell cycle. The cell cycle is highly regulated by numerous mechanisms ensuring orderly and coordinated cell division. The present review discusses current concepts related to regulation of the cell cycle and new therapeutic options that target aspects of the cell cycle.

Figure 1)

Cell cycle steps (G0, G1, S and M) and their associated cyclin-dependent kinase (CDK)-cyclin complex holoenzyme and CDK inhibitors. There are two families of CDK inhibitors: inhibitors of CDL 4 (INK4) (p15, p16) and CDK interacting protein/inhibitory protein (Cip/Kip) (p21, p27)

Figure 2)

Phosphatidylinositol 3-kinase (PI3K) intracellular signalling pathway. + Activation through phosphorylation; mTOR Mammalian target of rapamycin; PDK1 Phosphoinositide-dependent kinase 1; PIP2 Phosphatidylinositol 4,5-bisphosphate; PIP3 Phosphatidylinositol 3,4,5-trisphosphate

Figure 3)

Mitogen-activated protein kinase (MAPK) intracellular signalling pathway. After binding of growth hormone (epidermal growth factor, platelet-derived growth factor, fibroblast growth factor-2, insulin-like growth factor-1) to its tyrosine kinase receptor, the receptor becomes activated as a protein tyrosine kinase (PTK). PTK undergoes autophosphorylation at multiple tyrosine residues, which interacts with signalling proteins, in turn activating Ras, a low molecular weight G-protein. Ras leads to activation of MAPK through protein kinase cascade. Thereafter, MAPK induces the transcription of proto-oncogenes (c-fos, c-myc, c-myb, b-myb, ras)

Figure 4)

Overview of the most important steps of cell cycle regulation. The key regulatory proteins are the cyclin-dependent kinase (CDK) proteins, which are activated at specific time points of the cell cycle. To be active, CDK needs association with cyclin to form a holoenzyme complex. Different cyclins are required at different steps of the cell cycle. CDK activity is also regulated by cell cycle inhibitory proteins called cyclin dependent kinase inhibitors (CKIs), which conteract CDK activity. Also shown are proto-oncogenes: c-fos, c-myb, c-myc and ras. Their gene products play a major role in the expression of specific regulatory proteins for the progression of the cell cycle. CAK CDK-activating kinase; GAX Growth arrest-specific homeobox; MPF Mitosis-promoting factor; PCNA Proliferating cell nuclear antigen; pRB Retinoblastoma gene product; TGF-β Transforming growth factor-beta

Figure 5)

Principal sites of action of antiproliferative drugs

Figure 6)

Antiproliferative effects of sirolimus. 4E-BP1 Eukaryotic initiation factor 4E binding protein; CDK Cyclin-dependent kinase; eIF-4E Eukaryotic initiation factor 4E; FKBP12 FK506 binding protein, 12 kDa; mTOR Mammalian target of rapamycin; PI3K Phosphatidylinositol 3-kinase

Figure 7)

Anti-inflammatory effect of sirolimus. EMAP Endothelial monocyte-activating polypeptide; mRNA Messenger RNA; VSMC Vascular smooth muscle cell

Figure 8)

Mechanisms of action of antisense oligodeoxynucleotides (ODN), ribozyme and decoy ODN gene therapy. mRNA Messenger RNA; TF Transcription factor. Adapted from reference