Caffeoylxanthiazonoside exerts cardioprotective effects during chronic heart failure via inhibition of inflammatory responses in cardiac cells

Abstract

Caffeoylxanthiazonoside (CYT) is an active constituent isolated from the fruit of the Xanthium strumarium L plant. The aim of the present study was to investigate the cardioprotective effects of oral administration of CYT on chronic heart failure (CHF) and its underlying mechanisms. A rat model of CHF was first established, and cardiac function indices, including the heart/body weight index, left heart/body weight index, fractional shortening (FS), ejection fraction (EF), cardiac output (CO) and heart rate (HR), were subsequently determined by cardiac ultrasound. Serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK), and the levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in heart tissues and cardiac microvascular endothelial cells (CMECs) were determined using ELISA. In addition, the protein expression levels of nuclear factor-κB (NF-κB) signaling pathway members were determined by western blotting in CMECs. The results demonstrated that oral administration of 10, 20, 40 mg/kg CYT significantly reduced cardiac hypertrophy and reversed FS, EF, CO and HR when compared with CHF model rats. In addition, CYT administration significantly decreased the levels of TNF-α, IL-6 and IL-1β in heart tissues, as well as serum LDH and CK levels. Furthermore, exposure of CMECs to 20, 40 and 80 µg/ml CYT significantly decreased the production of TNF-α, IL-1β and IL-6. The protein expression levels of cytoplasmic NF-κB p65 and IκB were upregulated, while nuclear NF-κB p65 was downregulated following treatment of CMECs with 20, 40 and 80 µg/ml CYT when compared with untreated CHF model controls. In conclusion, the results of the current study suggest that CYT demonstrates cardioprotective effects in CHF model rats by suppressing the expression of pro-inflammatory cytokines and the NF-κB signaling pathway.

Keywords: Xanthium strumarium L.; caffeoylxanthiazonoside; cardioprotective effects; inflammatory cytokines; nuclear factor-κB pathway.

Figure 1.

Chemical structure of caffeoylxanthiazonoside.

Figure 2.

Effect of caffeoylxanthiazonoside on (A) heart weight/body weight and (B) left heart weight/body weight indexes in CHF model rats. The results are expressed as mean ± standard deviation (n=10). ^##P<0.01 vs. sham group; *P<0.05; **P<0.01 vs. CHF model group. CHF, chronic heart failure.

Figure 3.

Effect of caffeoylxanthiazonoside on (A) EF, (B) FS, (C) HR and (D) CO indexes in CHF model rats. The results are expressed as the mean ± standard deviation (n=10). ^##P<0.01 vs. sham group; *P<0.05 and **P<0.01 vs. CHF model group. EF, ejection fraction; FS, fractional shortening; HR, heart rate; cardiac output; CHF, chronic heart failure; BPM, beats per minute.

Figure 4.

Effect of caffeoylxanthiazonoside on (A) TNF-α, (B) IL-1β and (C) IL-6 protein levels in the heart tissues from CHF model rats. The results are expressed as the mean ± standard deviation (n=10). ^##P<0.01 vs. sham group; **P<0.01 vs. CHF model group. TNF-α, tumor necrosis factor-α; IL, interleukin; CHF, chronic heart failure.

Figure 5.

Effect of caffeoylxanthiazonoside on serum (A) CK and (B) LDH levels in CHF model rats. The results are expressed as the mean ± standard deviation (n=10). ^##P<0.01 vs. sham group; **P<0.01 vs. CHF model group. CK, creatine kinase; LDH, lactate dehydrogenase; CHF, chronic heart failure.

Figure 6.

Effect of caffeoylxanthiazonoside on (A) TNF-α, (B) IL-1β and (C) IL-6 protein levels in LPS-stimulated CMECs. The results are expressed as the mean ± standard deviation (n=4). ^##P<0.01 vs. control group; **P<0.01 vs. model group. TNF-α, tumor necrosis factor-α; IL, interleukin; LPS, lipopolysaccharide; CMECs, cardiac microvascular endothelial cells.

Figure 7.

Effect of caffeoylxanthiazonoside on the protein expression levels of NF-κB signaling pathway proteins, NF-κB p65 and IκB, in LPS-stimulated CMECs, as determined by western blotting analysis. NF-κB, nuclear factor-κB; LPS, lipopolysaccharide; CMECs, cardiac microvascular endothelial cells; (N), nuclear; (C), cytoplasmic.