Atherosclerosis 184 (2006) 53–62 Ursolic acid inhibits neointima formation in the rat carotid artery injury model Mayte Pozo, Virginia Castilla, Cristina Gutierrez, Rosario de Nicol´ as, Jes´ us Egido, Jes ´ us Gonz´ alez-Cabrero ∗ Research Unit, Vascular Pathology Laboratory, Fundaci´ on Jim´ enez D´ ıaz, Universidad Aut´ onoma, Avenida Reyes Cat´ olicos, 2, 28040 Madrid, Spain Received 1 October 2004; received in revised form 23 March 2005; accepted 5 April 2005 Available online 25 May 2005 Abstract Triterpenoids are natural compounds that are found in a large variety of plants and vegetarian foods, and are used for medicinal purposes in many Asian countries. Pentacyclic triterpenes, such as ursolic acid, have been reported to exhibit anticancer and anti-inflammatory properties. The present study was designed to assess the effects of ursolic acid in the migration and proliferation of vascular smooth muscle cells (VSMC), and in a vascular injury model. The exposure of VSMC to ursolic acid results in a chemotaxis inhibition, in a reduction of the expression of proliferating cell nuclear antigen (PCNA) and in a disorganization of -tubulin and vimentin cytoskeletal proteins. Administration of ursolic acid in the rat carotid balloon catheter injury model shows a significant inhibition of neointimal hyperplasia. Thus, we have demonstrated that daily doses of 6 mg/kg body weight for 10 days reduce both the ratio of intimal to medial areas and the degree of stenosis by 80%, and suppress the expression of PCNA in both neointima and media. These results suggest that pentacyclic triterpenes may be of potential therapeutic value in vascular injury, and a possible treatment strategy for the prevention of the progression of atherosclerosis and restenosis after angioplasty. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Migration; Proliferation; Vascular smooth muscle cell; Neointima; Carotid 1. Introduction Atherosclerosis has become to be recognized as a chronic inflammatory disease, from the early stages to its ultimate complications, involving both humoral and cellular mechanisms [1–3]. The development and progression of many vascular diseases are characterized by the abnormal migration and proliferation of vascular smooth muscle cells (VSMC), being key events underlying atherosclerotic conditions [4–6]. These cellular responses to vascular injury culminate in clinical complications such as neointimal hyper- plasia, which has been identified as one of the mechanisms of restenosis after percutaneous transluminal coronary angio- plasty (PTCA). This luminal narrowing remodeling process occurs in 30–50% of patients, limiting the long-term success ∗ Corresponding author. Tel.: +34 1 550 4800x3168; fax: +34 1 544 2636. E-mail address: jgonzaleza@fjd.es (J. Gonz´ alez-Cabrero). of that technique [5–7]. Experimental models in various ani- mal species have been used to study the pathological intimal formation as a response of acute vessel wall damage. The rat carotid artery injury after angioplasty is still one of the most convenient, rapid and thoroughly investigated models for the assessment of new drugs into the cellular and molecular mechanisms and treatment of intimal hyperplasia [5,8,9]. Pentacyclic triterpenes are naturally abundant compounds, widely distributed in plants, which are found in a large vari- ety of vegetarian foods, present a minimal toxicity, and have been used in the traditional medicine of many Asian coun- tries [10–13]. Triterpenoic acids, such as ursolic, betulinic and oleanolic, have been recently considered of interest in oncology because they exhibit an antineoplastic activity on several kind of cancers, including inhibition of tumorigen- esis, antimutagenic, antiangiogenic and antiviral properties [10,11,13–15]. Moreover, it has also been demonstrated that these natural products exert anti-inflammatory effects, such 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.04.014