Protective mechanism of total flavonoids from Chrysanthemum morifolium in mice with cardiac hypertrophy based on Notch1 signaling pathway

Abstract

Objective \nTo investigate the protective effect of total flavonoids from Chrysanthemum morifolium in mice with isoprenaline (ISO)-induced cardiac hypertrophy and its mechanism. \n \n \nMethods \nForty male mice were randomly divided into the control group, total flavonoids group, model group and treatment group, 10 mice in each group. Mice in the total flavonoids group and treatment group were given total flavonoids (100 mg/kg) by gavage for 14 days, and those in the control group and model group were given isotonic NaCl solution by gavage. Mice in the model group and treatment group were subcutaneously injected with ISO (5 mg/kg, 0.5 mL) for 7 consecutive days to establish a mouse model of cardiac hypertrophy on 8 d, and those in the control group and total flavonoids group received the same volume of isotonic NaCl solution by subcutaneous injection. The levels of left ventricular ejection fraction (LVEF), left ventricular short axis fractional shortening (LVFS), left ventricular mass index (LVMI), heart mass index (HMI), and heart weight/tibia length (HW/TL) were calculated. The contents of superoxide dismutase (SOD), malondialdehyde and reactive oxygen species were compared. The mRNA expressions of Collagen-1, Notch1, Hes1, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), Nox4 and Nrf2 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). \n \n \nResults \nThe levels of LVEF, LVFS, LVMI, HMI, HW/TL, SOD, malondialdehyde and reactive oxygen species among the four groups were significantly different (F = 62.114, 18.814, 59.824, 66.375, 48.362, 59.677, 46.195, 48.257; all P < 0.001). Compared with the control group, the levels of LVEF, LVFS and SOD decreased, and the levels of LVMI, HMI, HW/TL, malondialdehyde and reactive oxygen species increased remarkably in the model group (all P < 0.05). The levels of LVEF [(56 ± 6)% vs. (38 ± 5)%], LVFS [(32 ± 5)% vs. (22 ± 4)%] and SOD were higher, and the levels of LVMI [(4.1 ± 0.4) mg/g vs. (5.8 ± 0.5) mg/g], HMI [(5.3 ± 1.1) mg/g vs. (6.5 ± 0.6) mg/g], HW/TL [(9.8 ± 1.2) mg/mm vs. (12.4 ± 1.3) mg/mm], malondialdehyde and reactive oxygen species were lower in the treatment group than in the model group (all P < 0.05). The mRNA expressions of Collagen-1, Notch1, Hes1, β-MHC, ANP, Nox4 and Nrf2 among the four groups were significantly different (F = 85.372, 43.865, 69.841, 36.358, 23.964, 48.354, 57.781; all P < 0.001). The mRNA expressions of Collagen-1, Notch1, Hes1, β-MHC, ANP and Nox4 obviously up-regulated, and the Nrf2 mRNA expression observably down-regulated in the model group as compared with the control group (all P < 0.05). The mRNA expressions of Collagen-1, Notch1, Hes1, β-MHC, ANP and Nox4 were lower, and the Nrf2 mRNA expression was higher in the treatment group than in the model group (all P < 0.05). \n \n \nConclusion \nTotal flavonoids in Chrysanthemum morifolium can significantly alleviate ISO-induced cardiac hypertrophy, which may be related to the blockade of Notch signaling pathway, reduction of myocardial oxidative stress injury and inhibition of myocardial fibrosis. \n \n \nKey words: \nCardiomyopathy, hypertrophic;\xa0Chrysanthemum morifolium;\xa0Total flavonoids;\xa0Notch1 signaling pathway;\xa0Mice