Cinnamaldehyde exerts vasculoprotective effects in hypercholestrolemic rabbits
The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allocated to four groups at random: control, fed with standard rabbit chow; CIN, fed with standard diet and administered CIN; HCD, fed with 1% cholesterol-enriched diet; and HCD-CIN, fed with HCD and treated with CIN. CIN was orally given at a dose of (10 mg/kg/day) concomitantly with each diet type from day 1 until the termination of the experimental protocol (4 weeks). HCD elicited significant elevations in serum levels of total cholesterol (TC), triglycerides (TGs), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) compared with control rabbits. Moreover, aortic levels of nitric oxide metabolites (NOx) and antioxidant enzyme activities were significantly lower, while aortic levels of malondialdehyde (MDA) and myeloperoxidase (MPO) activity were significantly higher, in HCD-fed rabbits relative to control animals. CIN administration mitigated or completely reversed HCD-induced metabolic alterations, vascular oxidative stress, and inflammation. Moreover, CIN ameliorated HCD-induced vascular functional and structural irregularities. Aortic rings from HCD-CIN group showed improved relaxation to acetylcholine compared to aortas from HCD group. Moreover, CIN decreased atherosclerotic lipid deposition and intima/media (I/M) ratio of HCD aortas. CIN-mediated effects might be related to its ability to attenuate the elevated aortic mRNA expression of cholesteryl ester transfer protein (CETP) and MPO in HCD group. Interestingly, the vasculoprotective effects of CIN treatment in the current study do not seem to be mediated via Nrf2-dependent mechanisms. In conclusion, CIN may mitigate the development of atherosclerosis in hypercholestrolemic rabbits via cholesterol-lowering, antiinflammatory and antioxidant activities.
KeywordsCinnamaldehyde Cholesterol Rabbits Lipid profile Oxidative stress CETP Nrf2 Endothelial dysfunction
Author contribution statement
ON, GS, ME, and GMS conceived and designed research. ON, GS, and ME conducted experiments. GS analyzed data. ON and GS wrote the manuscript. GS, ME, and GMS revised the manuscript. MA performed pathological assessments. All authors read and approved the manuscript.
Compliance with ethical standards
All institutional and national guidelines for the care and use of laboratory animals were followed.
Conflict of interest
The authors declare no conflict of interest.
- Blaak EE, Van Baak MA, Kemerink GJ, Pakbiers MT, Heidendal GA, Saris WH (1994) Beta-adrenergic stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men. Am J Phys 267(2 Pt 1):E306–E315Google Scholar
- Flores-Castillo C, Zamora-Perez JA, Carreon-Torres E, Arzola-Paniagua A, Aguilar-Salinas C, Lopez-Olmos V et al (2015) Atorvastatin and fenofibrate combination induces the predominance of the large HDL subclasses and increased apo AI fractional catabolic rates in New Zealand white rabbits with exogenous hypercholesterolemia. Fundam Clin Pharmacol 29(4):362–370CrossRefGoogle Scholar
- Howden R (2013) Nrf2 and cardiovascular defense. Oxidative Med Cell Longev 2013:104308Google Scholar
- Kawabata F, Inoue N, Yazawa S, Kawada T, Inoue K, Fushiki T (2006) Effects of CH-19 sweet, a non-pungent cultivar of red pepper, in decreasing the body weight and suppressing body fat accumulation by sympathetic nerve activation in humans. Biosci Biotechnol Biochem 70(12):2824–2835CrossRefGoogle Scholar
- Khare P, Jagtap S, Jain Y, Baboota RK, Mangal P, Boparai RK, Bhutani KK, Sharma SS, Premkumar LS, Kondepudi KK, Chopra K, Bishnoi M (2016) Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice. Biofactors 42(2):201–211PubMedGoogle Scholar
- Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS (2008) Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kappaB activation: effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 229(2):161–171CrossRefGoogle Scholar
- Meakin PJ, Chowdhry S, Sharma RS, Ashford FB, Walsh SV, McCrimmon RJ, Dinkova-Kostova AT, Dillon JF, Hayes JD, Ashford ML (2014) Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. Mol Cell Biol 34(17):3305–3320CrossRefGoogle Scholar
- Messier EM, Day BJ, Bahmed K, Kleeberger SR, Tuder RM, Bowler RP, Chu HW, Mason RJ, Kosmider B (2013) N-acetylcysteine protects murine alveolar type II cells from cigarette smoke injury in a nuclear erythroid 2-related factor-2-independent manner. Am J Respir Cell Mol Biol 48(5):559–567CrossRefGoogle Scholar
- Mukherjee S, Coaxum SD, Maleque M, Das SK (2001) Effects of oxidized low density lipoprotein on nitric oxide synthetase and protein kinase C activities in bovine endothelial cells. Cell Mol Biol (Noisy-le-grand) 47(6):1051–1058Google Scholar
- Pape ME, Rehberg EF, Marotti KR, Melchior GW (1991) Molecular cloning, sequence, and expression of cynomolgus monkey cholesteryl ester transfer protein. Inverse correlation between hepatic cholesteryl ester transfer protein mRNA levels and plasma high density lipoprotein levels. Arterioscler Thromb 11(6):1759–1771CrossRefGoogle Scholar
- Singh A, Khan SA, Choudhary R, Bodakhe SH (2016) Cinnamaldehyde attenuates cataractogenesis via restoration of hypertension and oxidative stress in fructose-fed hypertensive rats. Aust J Pharm 19(2):137–144Google Scholar
- Yeh M, Gharavi NM, Choi J, Hsieh X, Reed E, Mouillesseaux KP, Cole AL, Reddy ST, Berliner JA (2004) Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway. J Biol Chem 279(29):30175–30181CrossRefGoogle Scholar
- Zhang J, Niimi M, Yang D, Liang J, Xu J, Kimura T, Mathew AV, Guo Y, Fan Y, Zhu T, Song J, Ackermann R, Koike Y, Schwendeman A, Lai L, Pennathur S, Garcia-Barrio M, Fan J, Chen YE (2017) Deficiency of cholesteryl ester transfer protein protects against atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 37(6):1068–1075CrossRefGoogle Scholar