NICD/Hes1 affects angiogenesis in the ischemic myocardium of myocardial infarction mice

doi:10.12307/2023.588

Abstract

Abstract: BACKGROUND: Myocardial ischemia is one of the main causes of cardiac function impairment after myocardial infarction. Notch is involved in the process of angiogenesis, but whether Notch intracellular domain (NICD)/Hes1 is involved in myocardial angiogenesis after myocardial infarction has not been studied.
OBJECTIVE: To study the effect of NICD /Hes1 pathway on cardiac function and angiogenesis in the ischemic myocardium of myocardial infarction mice with the aid of RO4929097, a Notch γ secretase inhibitor.
METHODS: C57BL/6 mice were randomized into sham, model and RO4929097 groups, with 10 mice in each group. Myocardial infarction model was established in the latter two groups by ligating the left anterior descending coronary artery of C57BL/6 mice. Mice in the RO4929097 group were administered RO4929097 by gavage at the dose of 10 mg/(kg·d) on day 2 after surgery, and those in the sham and model groups were given an equal volume of saline by gavage for 20 days. On day 21, mice were examined by ultrasound for left ventricular ejection fraction, Matson staining for myocardial infarct area and pathohistological changes and immunofluorescence for CD31 in ischemic myocardium. Enzyme-linked immunofluorescence was used to detect the levels of serum vascular endothelial growth factor and basic fibroblast growth factor. Western blot assay was used to detect the expression of hypoxia-inducible factor 1α, cardiotrophin 1, NICD and Hes1 in myocardial tissue.
RESULTS AND CONCLUSION: The left ventricular ejection fraction value in the model group was significantly lower than that in the sham group (P < 0.001), while compared with the model group, the left ventricular ejection fraction value was significantly lowered in the RO4929097 group (P < 0.05). Masson staining revealed an significantly increased infarct size in the model group and RO4929097 group compared with the sham group (P < 0.001) as well as an obviously increased infarct size in the RO4929097 group compared with the model group (P < 0.05). The mean absorbance value of CD31 significantly increased in the model group compared with the sham group (P < 0.001) and significantly decreased in the RO4929097 group compared with the model group (P < 0.001). Compared with the sham group, the levels of serum vascular endothelial growth factor and basic fibroblast growth factor significantly increased in the model and RO4929097 groups (P < 0.05); and the levels of these two factors were significantly higher in the RO4929097 group than the model group (P < 0.01). The protein expression levels of hypoxia-inducible factor 1α, cardiotrophin 1 were significantly increased in the model group compared with the sham group (P < 0.01) but decreased in the RO492909 group. The protein expression of NICD significantly increased in the model group compared with the sham group (P < 0.01) but decreased in the RO492909 group compared with the model group (P < 0.01). Compared with the sham group, the level of Hes1 was significantly decreased in the RO492909 group (P < 0.05). To conclude, RO4929097 may decrease NICD/Hes1 expression by inhibiting Notchγ secretase activity, thereby reducing ischemic myocardial revascularization and decreasing left ventricular ejection fraction in mice with myocardial infarction.

Key words: myocardial infarction, ischemic myocardium, angiogenesis, NICD, Hes1

CLC Number:

Lu Pengfei, Shi Weili. NICD/Hes1 affects angiogenesis in the ischemic myocardium of myocardial infarction mice[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(23): 3635-3639.

Figures/Tables 4

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