Advances in Clinical and Experimental Medicine
2018, vol. 27, nr 12, December, p. 1631–1636
Publication type: original article
All-trans retinoic acid effectively reduces atheroma plaque size in a rabbit model of high-fat-induced atherosclerosis
1 Solid Tumor Research Center, Urmia University of Medical Sciences, Iran
2 Student Research Committee, Urmia University of Medical Sciences, Iran
3 Department of Microbiology, Veterinary Faculty, Urmia University, Iran
4 Department of Pathology, Faculty of Medicine, Urmia University of Medical Sciences, Iran
Background. Atherosclerosis (AS) is one of the most prevalent causes of death around the world. Since there are different types of risk factors, different types of medications focus on preventing atheromas and plaques from establishing or on preventing established plaques from growing.
Objectives. The aim of this study was to evaluate the effect of all-trans retinoic acid (atRA) on AS in a rabbit model of fat-induced AS.
Material and Methods. Atherosclerosis was induced by a high-fat diet (HFD) for 75 days. Thirty rabbits were randomly divided into 5 groups. Group 1 was the negative control group and received a normal diet. The animals in the other groups were fed a HFD. Group 2 (the AS positive control group) received no drugs, Group 3 received atorvastatin orally (20 mg/kg/day), Group 4 received atRA (5 mg/kg/day, orally), and Group 5 received both drugs. All medications were started on day 45 and continued until the end of the study. Fasting blood samples were obtained for lipid profile evaluation. The aorta sections were evaluated for maximum wall and intima thickness.
Results. Oral administration of atRA, atorvastatin or their combination significantly improved serum lipid profile (p < 0.001). Atorvastatin and atRA significantly decreased serum total cholesterol and LDL-cholesterol levels in HFD (p < 0.001). No difference was found in serum HDL-cholesterol levels among the studied groups. The HFD group (Group 2 – positive control) showed significant intima irregularities with fat deposition and foamy macrophage accumulation (atheroma). Administration of atRA and atorvastatin significantly decreased the size of atherosclerotic plaques (intima thickness). The maximum vessel wall and intima thickness were significantly decreased after atRA and atorvastatin administration (p < 0.001). No difference was found between atRA and atorvastatin effectiveness, but combination therapy significantly decreased AS size in comparison to using either of the drugs alone (p < 0.001).
Conclusion. In reducing AS plaque size, atRA is as effective as atorvastatin. Additionally, the combination therapy of atRA and atorvastatin decreased AS size much more effectively, showing their synergistic effect. atRA can also improve the serum lipid profile.
atherosclerosis, high fat diet, all-trans retinoic acid
- Rezaee-Zavareh MS, Tohidi M, Sabouri A, Ramezani-Binabaj M, Sadeghi-Ghahrodi M, Einollahi B. Infectious and coronary artery disease. ARYA Atheroscler. 2016;12(1):41–49.
- Zhou B, Pan Y, Hu Z, et al. All-trans-retinoic acid ameliorated high fat diet-induced atherosclerosis in rabbits by inhibiting platelet activation and inflammation. J Biomed Biotechnol. 2012;2012:259693.
- Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–241.
- Talavera-Garcia E, Delgado-Lista J, Garcia-Rios A, et al. Influence of obesity and metabolic disease on carotid atherosclerosis in patients with coronary artery disease (CordioPrev Study). PLoS One. 2016;11(4):e0153096.
- Pellegrini C, Columbaro M, Capanni C, et al. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget. 2015;6(30):29914–29928.
- Swift J, Ivanovska IL, Buxboim A, et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013;341(6149):1240104.
- Jiang SJ, Campbell LA, Berry MW, Rosenfeld ME, Kuo CC. Retinoic acid prevents Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis. Microbes Infect. 2008;10(12–13):1393–1397.
- Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996;10(9):940–954.
- Guleria RS, Singh AB, Nizamutdinova IT, et al. Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats. J Mol Cell Cardiol. 2013;57:106–118.
- Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP. All-trans retinoic acid inhibits type-1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Diabetes. 2009;58(1):146–155.
- Amengual J, Ribot J, Bonet ML, Palou A. Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice. Obesity. 2008;16(3):585–591.
- Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol. 2009;29(12):3286–3296.
- Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204(8):1765–1774.
- Herdeg C, Oberhoff M, Baumbach A, et al. Effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery. Cardiovasc Res. 2003;57(2):544–553.
- Tehrani S, Mobarrez F, Antovic A, et al. Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia. Thromb Res. 2010;126(3):e225–231.
- Chockalingam P, Vinayagam NS, Chockalingam V, Chockalingam A. Remarkable regression of coronary atherosclerosis: An interplay of pharmacotherapeutic and lifestyle factors. Ind Heart J. 2016;68(2):188–189.
- Puri R, Nissen SE, Ballantyne CM, et al. Factors underlying regression of coronary atheroma with potent statin therapy. Eur Heart J. 2013;34(24):1818–1825.
- Nissen SE, Nicholls SJ, Sipahi I, et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID trial. JAMA. 2006;295(13):1556–1565.
- Amengual J, Ribot J, Bonet ML, Palou A. Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice. Obesity (Silver Spring). 2008;16(3):585–591.
- Rebe C, Raveneau M, Chevriaux A, et al. Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor alpha pathway increases the clearance of apoptotic cells by human macrophages. Circ Res. 2009;105(4):393–401.
- Imaizumi T, Yagihashi N, Kubota K, et al. Expression of retinoic acid-inducible gene-I (RIG-I) in macrophages: Possible involvement of RIG-I in atherosclerosis. J Atheroscler Thromb. 2007;14(2):51–55.
- Kim YM, Kim JH, Park SW, Kim HJ, Chang KC. Retinoic acid inhibits tissue factor and HMGB1 via modulation of AMPK activity in TNF-α activated endothelial cells and LPS-injected mice. Atherosclerosis. 2015;241(2):615–623.
- Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340(2):115–126.
- Bilbija D, Elmabsout AA, Sagave J, et al. Expression of retinoic acid target genes in coronary artery disease. Int J Mol Med. 2014;33(3):677–686.