Rosmarinic Acid Suppresses Abdominal Aortic Aneurysm Progression in Apolipoprotein E-deficient Mice

Abstract

An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice via infusion of angiotensin II for 4 wks. Rosmarinic acid, salvianolic acid C, salvianolic acid B, or doxycycline as a positive control was provided daily through intraperitoneal injection. Administration of rosmarinic acid was found to decrease the thickness of the aortic wall, as determined by histopathological assay. Rosmarinic acid also exhibited protection against elastin fragmentation in aortic media and down-regulated cell apoptosis and proliferation in the aortic adventitia. Infiltration of macrophages, T lymphocytes, and neutrophils in aortic aneurysms was found, especially at the aortic adventitia. Rosmarinic acid, salvianolic acid C, or salvianolic acid B inhibited the infiltration on macrophages specifically, but these compounds did not influence T lymphocytes and neutrophils. Expression of matrix metalloproteinase 9 and macrophage migration inhibitory factor significantly increased in aortic aneurysms. Rosmarinic acid and salvianolic acid C decreased the expression of matrix metalloproteinase-9 in media, and rosmarinic acid also tended to reduce migration inhibitory factor expression. Further then, partial least squares-discriminate analysis was used to classify metabolic changes among different treatments. Rosmarinic acid affected most of the metabolites in the biosynthesis of the citrate cycle, fatty acid pathway significantly. Our present study on mice demonstrated that rosmarinic acid inhibited multiple pathological processes, which were the key features important in abdominal aortic aneurysm formation. Further study on rosmarinic acid, the novel candidate for aneurysmal therapy, should be undertaken to determine its potential for clinical use.

Key words

abdominal aortic aneurysm - rosmarinic acid - salvianolic acid C - salvianolic acid B - Salvia miltiorrhiza Bunge - Labiatae

Publication History

Received: 02 April 2021

Accepted after revision: 17 September 2021

Article published online:
05 November 2021

• References

• 1 Drasković M, Misović S, Jevtić M, Sarac M. Abdominal aortic aneurysm–rupture of the anterior wall. Med Pregl 2007; 60: 80-84
• 2 Pande RL, Beckman JA. Abdominal aortic aneurysm: populations at risk and how to screen. J Vasc Interv Radiol 2008; 19: 2-8
• 3 Maegdefessel L, Dalman RL, Tsao PS. Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations. Annu Rev Med 2014; 65: 49-62
• 4 Mattes E, Davis TM, Yang D, Ridley D, Lund H, Norman PE. Prevalence of abdominal aortic aneurysms in men with diabetes. Med J Aust 1997; 166: 630-633
• 5 Kontopodis N, Lioudaki S, Pantidis D, Papadopoulos G, Georgakarakos E, Ioannou CV. Advances in determining abdominal aortic aneurysm size and growth. World J Radiol 2016; 8: 148-158
• 6 Baxter BT, Terrin MC, Dalman RL. Medical management of small abdominal aortic aneurysms. Circulation 2008; 117: 1883-1889
• 7 Ouriel K. Randomized clinical trials of endovascular repair versus surveillance for treatment of small abdominal aortic aneurysms. J Endovasc Ther 2009; 16: I94-105
• 8 Pande RL, Beckman JA. Abdominal aortic aneurysm: populations at risk and how to screen. J Vasc Interv Radiol 2008; 19: 2-8
• 9 Li H, Jiang W, Ren W, Guo D, Guo J, Wang X, Liu Y, Lan F, Du J, Zhang H. Downregulation of the yes-associated protein is associated with extracellular matrix disorders in ascending aortic aneurysms. Stem Cells Int 2016; 2016: 6786184
• 10 Davis FM, Rateri DL, Daugherty A. Mechanisms of aortic aneurysm formation: Translating preclinical studies into clinical therapies. Heart 2014; 100: 1498-1505
• 11 Vanderlaan PA, Reardon CA. Thematic review series: the immune system and atherogenesis. The unusual suspects: An overview of the minor leukocyte populations in atherosclerosis. J Lipid Res 2005; 46: 829-838
• 12 Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M, Ideishi M, Arakawa K. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension 1999; 33: 1399-1405
• 13 Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1995; 15: 1145-1151
• 14 Thompson RW, Curci JA, Ennis TL, Mao D, Pagano MB, Pham CT. Pathophysiology of abdominal aortic aneurysms: Insights from the elastase-induced model in mice with different genetic backgrounds. Ann NY Acad Sci 2006; 1085: 59-73
• 15 Su CY, Ming QL, Rahman K, Han T, Qin LP. Salvia miltiorrhiza: traditional medicinal uses, chemistry, and pharmacology. Chin J Nat Med 2015; 13: 163-182
• 16 Shi M, Huang F, Deng C, Wang Y, Kai G. Bioactivities, biosynthesis and biotechnological production of phenolic acids in Salvia miltiorrhiza. Crit Rev Food Sci Nutr 2019; 59: 953-964
• 17 Han J, Wang D, Ye L, Li P, Hao W, Chen X, Ma J, Wang B, Shang J, Li D, Zheng Q. Rosmarinic acid protects against inflammation and cardiomyocyte apoptosis during myocardial ischemia/reperfusion injury by activating peroxisome proliferator-activated receptor gamma. Front Pharmcol 2017; 8: 456
• 18 Daugherty A, Manning MW, Cassis LA. Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J Pharmacol 2001; 134: 865-870
• 19 Zweers MC, Peeters AC, Graafsma S, Kranendonk S, van der Vliet JA, den Heijer M, Schalkwijk J. Abdominal aortic aneurysm is associated with high serum levels of tenascin-X and decreased aneurysmal tissue tenascin-X. Circulation 2006; 113: 1702-1707
• 20 Zhang T, Xu J, Li D, Chen J, Shen X, Xu F, Teng F, Deng Y, Ma H, Zhang L, Zhang G, Zhang Z, Wu W, Liu X, Yang M, Jiang B, Guo D. Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice. Phytomedicine 2014; 21: 1137-1145
• 21 Marfella R, Di Filippo C, Laieta MT, Vestini R, Barbieri M, Sangiulo P, Crescenzi B, Ferraraccio F, Rossi F, DʼAmico M, Paolisso G. Effects of ubiquitin-proteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients. J Gerontol A Bio Sci Med Sci 2008; 63: 200-203
• 22 Wilson KA, Woodburn KR, Ruckley CV, Fowkes FG. Expansion rates of abdominal aortic aneurysm: current limitations in evaluation. Eur J Vasc Endovasc Surg 1997; 13: 521-526
• 23 Long A, Rouet L, Bissery A, Rossignol P, Mouradian D, Sapoval M. Compliance of abdominal aortic aneurysms evaluated by tissue Doppler imaging: correlation with aneurysm size. J Vasc Surg 2005; 42: 18-26
• 24 Guessous I, Periard D, Lorenzetti D, Cornuz J, Ghali WA. The efficacy of pharmacotherapy for decreasing the expansion rate of abdominal aortic aneurysms: A systematic review and meta-analysis. PLoS One 2008; 3: e1895
• 25 Johnson JA, Boerwinkle E, Zineh I, Chapman AB, Bailey K, Cooper-DeHoff RM, Gums J, Curry RW, Gong Y, Beitelshees AL, Schwartz G, Turner ST. Pharmacogenomics of antihypertensive drugs: Rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Am Heart J 2009; 157: 442-449
• 26 Mosorin M, Juvonen J, Biancari F, Satta J, Surcel HM, Leinonen M, Saikku P, Juvonen T. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: A randomized, double-blind, placebo-controlled pilot study. J Vasc Surg 2001; 34: 606-610
• 27 Youn J, Lee KH, Won J, Huh SJ, Yun HS, Cho WG, Paik DJ. Beneficial effects of rosmarinic acid on suppression of collagen induced arthritis. J Rheumatol 2003; 30: 1203-1207
• 28 Oh HA, Park CS, Ahn HJ, Park YS, Kim HM. Effect of Perilla frutescens var. acuta Kudo and rosmarinic acid on allergic inflammatory reactions. Exp Biol Med (Maywood) 2011; 236: 99-106
• 29 Chu X, Ci X, He J, Jiang L, Wei M, Cao Q, Guan M, Xie X, Deng X, He J. Effects of a natural prolyl oligopeptidase inhibitor, rosmarinic acid, on lipopolysaccharide-induced acute lung injury in mice. Molecules 2012; 17: 3586-3598
• 30 Jang AH, Kim TH, Kim GD, Park GS. Administration of rosmarinic acid ameliorated DNFB-induced atopic dermatitis like symptoms in NC/Nga mice. Toxicol Lett 2010; 196: S196
• 31 Jang AH, Kim TH, Kim GD, Kim JE, Kim HJ, Kim SS, Jin YH, Park YS, Park CS. Rosmarinic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice. Int Immunopharmacol 2011; 11: 1271-1277
• 32 Cheng AC, Lee MF, Tsai ML, Lai CS, Lee JH, Ho CT, Pan MH. Rosmanol potently induces apoptosis through both the mitochondrial apoptotic pathway and death receptor pathway in human colon adenocarcinoma COLO 205 cells. Food Chem Toxicol 2011; 49: 485-493
• 33 Karimi A, Milewicz DM. Structure of the elastin-contractile units in the thoracic aorta and how genes that cause thoracic aortic aneurysms and dissections disrupt this structure. Can J Cardiol 2016; 32: 26-34
• 34 Luciani GB, Favaro A, Casali G, Santini F, Mazzucco A. Reoperations for aortic aneurysm after the Ross procedure. J Heart Valve Dis 2005; 14: 766-773
• 35 Ruddy JM, Jones JA, Spinale FG, Ikonomidis JS. Regional heterogeneity within the aorta: Relevance to aneurysm disease. J Thorac Cardiovasc Surg 2008; 136: 1123-1130
• 36 Lohoefer F, Reeps C, Lipp C, Rudelius M, Zimmermann A, Ockert S, Eckstein HH, Pelisek J. Histopathological analysis of cellular localization of cathepsins in abdominal aortic aneurysm wall. Int J Exp Pathol 2012; 93: 252-258
• 37 Ailawadi G, Eliason JL, Upchurch jr. GR. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg 2003; 38: 584-588
• 38 Reynolds LP, Grazul-Bilska AT, Redmer DA. Angiogenesis in the corpus luteum. Endocrine 2000; 12: 1-9
• 39 Michel JB, Thaunat O, Houard X, Meilhac O, Caligiuri G, Nicoletti A. Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol 2007; 27: 1259-1268
• 40 Ciborowski M, Teul J, Martin-Ventura JL, Egido J, Barbas C. Metabolomics with LC-QTOF-MS permits the prediction of disease stage in aortic abdominal aneurysm based on plasma metabolic fingerprint. PLoS One 2012; 7: 31982
• 41 Takagi H, Matsui M, Umemoto T. A meta-analysis of clinical studies of statins for prevention of abdominal aortic aneurysm expansion. J Vasc Surg 2010; 52: 1675-1681