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Corosolic acid attenuates cardiac fibrosis following myocardial infarction in mice.

ABSTRACT: Corosolic acid (CRA) is a pentacyclic triterpenoid isolated from Lagerstroemia speciosa. The aim of the present study was to determine whether CRA reduces cardiac remodelling following myocardial infarction (MI) and to elucidate the underlying mechanisms. C57BL/6J mice were randomly divided into control (PBS?treated) or CRA?treated groups. After 14 days of pre?treatment, the mice were subjected to either sham surgery or permanent ligation of the left anterior descending artery. Following surgery, all animals were treated with PBS or CRA (10 or 20 mg/kg/day) for 4 weeks. After 4 weeks, echocardiographic, haemodynamic, gravimetric, histological and biochemical analyses were conducted. The results revealed that, upon MI, mice with CRA treatment exhibited decreased mortality rates, improved ventricular function and attenuated cardiac fibrosis compared with those in control mice. Furthermore, CRA treatment resulted in reduced oxidative stress, inflammation and apoptosis, as well as inhibited the transforming growth factor ?1/Smad signalling pathway activation in cardiac tissue. In vitro studies further indicated that inhibition of AMP?activated protein kinase ? (AMPK?) reversed the protective effect of CRA. In conclusion, the study revealed that CRA attenuated MI?induced cardiac fibrosis and dysfunction through modulation of inflammation and oxidative stress associated with AMPK?.

SUBMITTER: Wang ZP

PROVIDER: S-EPMC7138284 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Corosolic acid attenuates cardiac fibrosis following myocardial infarction in mice.

Wang Zhao-Peng ZP Che Yan Y Zhou Heng H Meng Yan-Yan YY Wu Hai-Ming HM Jin Ya-Ge YG Wu Qing-Qing QQ Wang Sha-Sha SS Yuan Yuan Y

International journal of molecular medicine 20200309 5

Corosolic acid (CRA) is a pentacyclic triterpenoid isolated from Lagerstroemia speciosa. The aim of the present study was to determine whether CRA reduces cardiac remodelling following myocardial infarction (MI) and to elucidate the underlying mechanisms. C57BL/6J mice were randomly divided into control (PBS‑treated) or CRA‑treated groups. After 14 days of pre‑treatment, the mice were subjected to either sham surgery or permanent ligation of the left anterior descending artery. Following surgery ...[more]

PMID: 32323841

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Project description:In spite of early interventions to treat acute myocardial infarction (MI), the occurrence of adverse cardiac remodeling following heart failure due to acute MI remains a clinical challenge. Thus, there is an increasing demand for the development of novel therapeutic agents capable of inhibiting the development of pathological ventricular remodeling. RNA-seq data analysis of acute MI rat models from GEO revealed that Runx1 was the most differentially expressed MI-related gene. In this study, we demonstrated that increased Runx1 expression under pathological conditions results in decreased cardiac contractile function. We identified dihydrolycorine, an alkaloid lycorine, as a promising inhibitor of Runx1. Our results showed that treatment with this drug could prevent adverse cardiac remodeling, as indicated by the downregulation of fibrotic genes using western blotting (collagen I, TGFβ, and p-smad3), downregulation of the apoptosis gene Bax, upregulation of the apoptosis gene Bcl-2, and improved cardiac functions, such as LVEF, LVSF, LVESD, and LVEDD. Additionally, dihydrolycorine treatment could rescue cardiomyocyte hypertrophy as demonstrated by wheat germ agglutinin staining, increased expression levels of the punctuate gap junction protein connexin 43, and decreased α-SMA expression, resulting in cardiomyocyte fibrosis in immunofluorescence staining. Molecular docking, binding modeling, and pull-down assays were used to identify potential dihydrolycorine-binding sites in Runx1. When Ad-sh-Runx1 was transfected into hypoxia-cardiomyocytes or injected into the hearts of MI rats, the cardioprotective effects of dihydrolycorine were abolished, and the normal electrophysiological activity of cardiomyocytes was disrupted. Taken together, the results of the present study indicate that dihydrolycorine may inhibit adverse cardiac remodeling after MI through the reduction of Runx1, suggesting that dihydrolycorine-mediated-Runx1 regulation might represent a novel therapeutic approach for adverse cardiac remodeling after MI.

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Corosolic acid attenuates cardiac fibrosis following myocardial infarction in mice.

Publications

Corosolic acid attenuates cardiac fibrosis following myocardial infarction in mice.

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