GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 75Gene Ther Mol Biol Vol 7, 75-89, 2003Gene therapy antiproliferative strategies againstcardiovascular diseaseReview ArticleMarisol Gascón-Irún, Silvia M. Sanz-González and Vicente Andrés*Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicinade Valencia, Spanish Council for Scientific Research (CSIC), Valencia, Spain__________________________________________________________________________________*Correspondence: Vicente Andrés, Ph.D; Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology andTherapy, Instituto de Biomedicina de Valencia, Spanish Council for Scientific Research (CSIC), C/ Jaime Roig, 11 46010 Valencia(SPAIN); Tel.: +34-963391752 (office), +34-963391751 (lab), Fax: +34-963690800; e-mail: vandres@ibv.csic.esKey words: atherosclerosis, restenosis, bypass graft failure, cell cycle, gene therapyList of abbreviations: apoE, apolipoprotein E; AP-1, activator protein-1; BrdU, 5-bromodeoxyuridine; CDK, cyclin-dependent kinase;CKI, CDK inhibitory protein; EC, endothelial cell; ERK, extracellular signal-regulated kinase; IVUS, intravascular ultrasound; JNK, c-jun NH 2 -terminal protein kinase; MAPK, mitogen-activated protein kinase; ODN, oligodeoxynucleotide; PCNA, proliferating cellnuclear antigen; PDGF, platelet-derived growth factor; pRb, retinoblastoma protein; PTCA, percutaneous transluminal angioplasty;SAPK, stress-activated protein kinase; TGF-β, transforming growth factor-β; VSMC, vascular smooth muscle cell.Received: 17 June 2003; Accepted: 27 June 2003; electronically published: July 2003SummaryExcessive cellular proliferation is thought to contribute to the pathogenesis of several forms of cardiovasculardisease (e. g., atherosclerosis, restenosis after angioplasty, and vessel bypass graft failure). Therefore, candidatetargets for the treatment of these disorders include cell cycle regulatory factors, such as cyclin-dependent kinases(CDKs), cyclins, CDK inhibitory proteins (CKIs), tumor suppressors, growth factors and their receptors, andtranscription factors. Importantly, animal models of atherosclerosis have demonstrated an inverse correlationbetween neointimal cell proliferation and atheroma size, suggesting that excessive cell growth prevails at the onsetof atherogenesis. Cell growth may also predominate at the onset of human atherosclerosis. Thus, given that affectedhumans often exhibit advanced atherosclerotic plaques when first diagnosed, the potential benefit ofantiproliferative strategies for the treatment of atherosclerosis in clinic is doubtful. The antiproliferativeapproaches used so far in the setting of vascular obstructive disease have focused on restenosis and graftatherosclerosis, during which neointimal hyperplasia is spatially localized and develops over a short period of time(typically 2-12 months). Vascular interventions, both endovascular and open surgical, allow minimally invasive,easily monitored gene delivery. Thus, gene therapy strategies are emerging as an attractive approach for thetreatment of vascular proliferative disease. In this review, we will discuss the use of gene therapy strategies againstcellular proliferation in animal models and clinical trials of cardiovascular disease.I. IntroductionLarge-scale clinical trials conducted over the lastdecades have allowed the identification of independentrisk factors that increase the prevalence and severity ofatherosclerosis (e. g., hypercholesterolemia, hypertension,smoking). Cardiovascular risk factors initiate andperpetuate an inflammatory response within the injuredarterial wall that promotes the development ofatherosclerotic plaques (Ross, 1999; Lusis, 2000; Dzau etal, 2002; Steinberg, 2002) (Figure 1). Chemokines andcytokines secreted by leukocytes that accumulate withinthe injured arterial wall promote their own proliferation, aswell as the growth and migration of the underlyingvascular smooth muscle cells (VSMCs) (Figure 2). Thisinflammatory response also plays a critical role duringrestenosis after angioplasty and graft atherosclerosis.Thus, understanding the molecular mechanisms thatcontrol hyperplastic growth of vascular cells should helpdevelop novel therapeutic strategies for the treatment ofvascular obstructive disease.Although arterial cell proliferation occurs in animalmodels during all phases of atherogenesis (Ross, 1999;Díez-Juan and Andrés, 2001; Cortés et al, 2002), studieswith hyperlipidemic rabbits have shown an inversecorrelation between atheroma size and cellularproliferation within the atheromatous plaque (Spraragen etal, 1962; McMillan and Stary, 1968; Rosenfeld and Ross,1990). Experimental angioplasty is also characterized by75