Cinnamaldehyde Mitigates Atherosclerosis Induced by High-Fat Diet via Modulation of Hyperlipidemia, Oxidative Stress, and Inflammation

Abstract

Atherosclerosis is a disease in which plaque builds up inside arteries. Cinnamaldehyde (Ci) has many biological properties that include anti-inflammatory and antioxidant activities. Thus, this study was designed to explore the protective effect of Ci against atherosclerosis induced by a high-fat diet (HFD) in Wistar rats. Atherosclerosis was induced by an oral administration of an HFD for 10 weeks. Atherosclerosis-induced rats were supplemented with Ci at a dose of 20 mg/kg bw dissolved in 0.5% dimethyl sulfoxide (DMSO), daily by oral gavage for the same period. Rats were divided into three groups of 10 rats each fed with (a) ND, (b) HFD, and (c) HFD+Ci, daily for 10 weeks. Treatment of rats with Ci significantly reduced the elevated levels of serum total cholesterol (T.Ch), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-Ch), very low-density lipoprotein-cholesterol (VLDL-Ch), and free fatty acids (FFAs) and significantly increased the lowered levels of high-density lipoprotein-cholesterol (HDL-Ch) level. Ci ameliorated the increased cardiovascular risk indices 1 and 2 and the decreased antiatherogenic index. Moreover, Ci reduced the elevated serum creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) activities. Ci also improved the heart antioxidant activities by decreasing malondialdehyde (MDA) and increasing glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (Gpx) activities. Furthermore, the supplementation with Ci downregulated the mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Thus, Ci successfully elicited a therapeutic impact against atherosclerosis induced by HFD via its hypolipidemic, antioxidant, and anti-inflammatory actions.

Figure 1

Experimental design for ND (normal diet), HFD (high-fat diet), HFD+Ci (high fat diet+cinnamaldehyde) groups.

Figure 2

Effect of cinnamaldehyde on the serum lipid profile, CVR indices, and AAI of rats fed with a high-fat diet. The changes in the values of (a) T.Ch, (b) TG, (c) HDL-Ch, (d) LDL-Ch, (e) VLDL-Ch, (f) FFAs, (g) CVR risk 1, (h) CVR risk 2, and (i) AAI among ND (normal diet), HFD (high-fat diet), HFD+Ci (high-fat diet+cinnamaldehyde) groups. Mean value is significant at ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 as compared to the normal diet group and at ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 as compared to the high-fat diet group. N.S.: not significant; cholesterol: Ch; LDL-cholesterol: low-density lipoprotein-cholesterol; HDL-cholesterol: high-density lipoprotein-cholesterol; VLDL-cholesterol: very low-density lipoprotein-cholesterol; cardiovascular risk factor 1 (cholesterol/HDL): cholesterol/high-density lipoprotein-cholesterol; cardiovascular risk factor 2 (LDL/HDL): low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol.

Figure 3

Impact of cinnamaldehyde on serum heart-function enzymes CK, CK-MB, AST, and LDH activities in high-fat-diet-feeding rats. The changes in the values of (a) CK, (b) CK-MB, (c) LDH, and (d) AST among ND (normal diet), HFD (high-fat diet), HFD+Ci (high-fat diet+cinnamaldehyde) groups. Mean value is significant at ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 as compared to the normal diet group and at ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 as compared to the high-fat diet group. N.S.: not significant; CK: creatine kinase; CK-MB: creatine kinase-MB; LDH: lactate dehydrogenase; AST: aspartate aminotransferase.

Figure 4

Effect of cinnamaldehyde on the heart oxidative stress and antioxidant defense system of rats fed with a high-fat diet. The changes in the values of (a) MDA, (b) GST, (c) SOD, (d) CAT, (e) GSH, and (f) GPx among ND (normal diet), HFD (high-fat diet), HFD+Ci (high-fat diet+cinnamaldehyde) groups. Mean value is significant at ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 as compared to the normal diet group and at ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 as compared to the high-fat diet group. N.S.: not significant; MDA: malondialdehyde; GST: glutathione S-transferase; SOD: superoxide dismutase; CAT: catalase; GSH: reduced glutathione; GPx: glutathione peroxidase.

Figure 5

Effect of cinnamaldehyde on IL-1β, IL-6, IL-17, and TNF-α inflammatory biomarkers of rats fed with a high-fat diet. The changes in the values of (a) IL-1β, (b) IL-6, (c) IL-17, and (d) TNF-α among ND (normal diet), HFD (high-fat diet), HFD+Ci (high-fat diet+cinnamaldehyde) groups. Mean value is significant at ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 as compared to the normal diet group and at ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 as compared to the high-fat diet group. N.S.: not significant; IL-1β: interleukin-1β; IL-6: interleukin-6; IL-17: interleukin-17; TNF-α: tumor necrosis factor-α.

Figure 6

Photomicrograph (a) of cardiac muscle sections of normal diet group showing arranged cardiac muscle fibers with vesicular nuclei (arrow). The fibers are branching and anastomose with each other. Photomicrograph (b) of cardiac muscle sections of HFD-administered group showing degenerated cardiac muscle with deposition of fat (intracytoplasmic fat vacuoles) (yellow arrow), mononuclear cellular infiltration (red arrow), degenerated wall of the congested artery and arterial wall with fat deposition (black arrow), degenerated wall of the congested artery, and focal necrosis and vacuoles in cardiomyocytes (black arrow); (c) cardiac muscle degeneration (yellow arrow) with infiltration of inflammatory cells (red arrow), and myocytes that lost their striations (black arrow) and pyknotic nuclei; and (d) severe degenerated cardiac muscle (yellow arrow) and fragmented cardiomyocytes and some of them lose their nuclei (black arrow), while others reveal pyknotic nuclei and mononuclear cellular infiltration (red arrow). Photomicrographs (e, f) of cardiac muscle sections of HFD-administered rats treated with cinnamaldehyde showed notable heart histological architecture and integrity improvement of the heart. H&E 400x.

Figure 7

Photomicrograph of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression-stained cardiac tissue section of (a) normal diet rats showing negative reaction (IL-1β and TNF-α; scale bar = 50 μm), (b) HFD-administered rats showing intense brown immunoreaction in the cytoplasm of cardiomyocytes (IL-1β and TNF-α; scale bar = 50 μm), and (c) HFD-administered rats treated with cinnamaldehyde showing week immunoreactions (IL-1β and TNF-α; scale bar = 50 μm). Column charts demonstrate the intensity of the brown immunoreaction (b). Mean value is significant at ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 as compared to the normal diet group and at ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 as compared to the high-fat diet group. N.S.: not significant.

Figure 8

Model of work showing the mitigation effect of cinnamaldehyde against high-fat-diet-induced atherosclerosis.