Astragaloside IV promotes cardiac remodeling after myocardial infarction by inhibiting DNMT3B-mediated Runx3 methylation via downregulating LncRNA MIRT1 expression

Jing Gao,Hong Zhang,Chunming Meng,Wei Zhang,Li Guan

doi:10.1590/fst.44721

Abstract

Astragaloside IV (AS-IV) has been shown to possess cardioprotective effect. However, the specific mechanism of AS-IV in myocardial infarction (MI) remains unclear. Our results showed that AS-IV intervention observably enhanced cell viability and reduced cell apoptosis, oxidative stress levels and inflammatory factor secretion. Expression of MIRT1 was significantly up-regulated in hypoxia-treated cells. In addition, ALCAM overexpression reversed the effects of AS-IV intervention on hypoxia-treated cell functions. MIRT1 facilitated Runx3 promoter methylation and its downregulated expression by recruiting DNA methyltransferase 3B (DNMT3B) to the Runx3 promoter region through binding with suppressor of Zeste 12 protein homolog (Suz12). Runx3 silencing reversed the effects of MIRT1 inhibition on hypoxia-treated cell functions. Betulinic acid suppressed the effects of AS-IV intervention on the behaviors of hypoxia-treated cells. AS-IV treatment improved the cardiac functions of mice with MI. Taken together, these findings demonstrated that AS-IV treatment inhibits DNMT3B-mediated Runx3 promoter methylation by restraining Suz12 expression and further blocks the NF-κB signaling pathway, and in turn improves the cardiac functions of mice with MI.

Highlights

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide (Lu et al, 2015)
Flow cytometry results showed that the apoptosis rate was significantly increased in hypoxia-treated cells, whereas Astragaloside IV (AS-IV) intervention could observably reduce the apoptosis rate of HL-1 cells induced by hypoxia in a dose-dependent manner (Figure 1D, E, P < 0.05)
superoxide dismutase (SOD) secretion was decreased, and MDA, IL-6 and tumor necrosis factor-α (TNF-α) secretion were elevated in hypoxia treated cells compared with the control group, while AS-IV intervention could reverse these effects, indicating that AS-IV in hypoxia-treated cells may play a role of anti-oxidant and anti-inflammatory (Figure 1F-I, P < 0.05)

Summary

Introduction

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide (Lu et al, 2015). The burden of MI has generally increased due to the aging of the world population, population growth, and rising prevalence of long-term survivors of MI (Pollard, 2000). The treatment of this disease requires further in-depth study of novel therapeutic drugs. AS-IV has been reported to have a protective effect on the heart and enhance angiogenesis and cardiac remodeling after MI (Cheng et al, 2019). AS-IV enhanced the cardioprotective effect of remote ischemic conditioning on MI induced heart failure and ventricular remodeling and was considered as a potential therapeutic agent to preserve cardiac function and improve MI prognosis (Cheng et al, 2016). The underlying mechanism through which AS-IV exerts cardioprotective effects remains unclear

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