Notopterol Protects against Heart Failure Post-myocardial Infarction via GSK3β-dependent Pathway Notopterol Protects against Heart Failure

Author:

Yang Cheng-Mei1,Shan Qing2,Wen Jia-Li3,Guo Jin-Min1,Yao Tian-Ming4

Affiliation:

1. the 960 Hospital

2. Weifang Medical University

3. Shenyang Pharmaceutical University

4. the 964 Hospital

Abstract

Abstract Introduction: Heart failure (HF), which frequently results from myocardial infarction (MI), leads to death and morbidity to a great extent globally, commonly developed from. Notopterol (NOT) is an active monomer extract obtained from Notopterygium incisum Ting ex H.T. Chang (N. incisum), a traditional Chinese medicine, that is extensively used in the clinical practice of cardiovascular disease and provides definite curative effects. NOT has been proven to be the most abundant constituent enriched in patients' serum and N. incisum ethanol extract. However, the role of NOT and its molecular target in HF remain unknown. Methods: In vivo, left anterior descending (LAD) ligation was conducted for MI induction and then for four weeks to induce HF. Mice were treated with NOT intragastrically for four weeks. Early (0.5 h post-MI) and delayed (12 h post-MI) pre-administration post-MI, as well as a therapeutictreatment after HF, were carried out. Echocardiography was used to assess heart function. H&E staining, wheat germ agglutinin (WGA), as well as Masson trichromatic heart stainings, were applied to evaluate cardiac remodeling, myocardial hypertrophy, and fibrosis, as well as the expression of molecules. In vitro, mouse HL1 cells were treated with NOT after Ang II-stimulation. We measured cardiomyocyte hypertrophythrough α-actinin immunofluorescence staining and hypertrophy gene expression. Meanwhile, phosphorylation of GSK3β is measured after NOT treatment. Then, GSK3β inhibitor 1-AKP was utilized for investigating NOT underlying pathway. Results:In vivo, early (0.5 h p-MI) and delayed (12 h p-MI) pretreatment of NOT alleviated cardiac dysfunction after MI and postponed the onset of HF. Intragastrical administration of NOT after HF prevented adverse cardiac remodeling and attenuated hypertrophy and fibrosis against cardiac injury, as well as inflammation. In vitro, NOT presented an anti-hypertrophy property in cultured HL1 cells subjected to AngⅡ-stimulation. NOT served as an inhibitor of GSK3β; it upregulated the inhibitory phosphorylation of GSK3β, and its beneficial action against heart hypertrophy is partially abolished by inhibiting GSK3β. Conclusion: Our studies show that NOT treatment prevented adverse cardiac remodeling, and attenuated hypertrophy and fibrosis, thereby effectively protecting against the development and progressionof HF. GSK3β pathways are involved in the anti-hypertrophy action of NOT.

Publisher

Research Square Platform LLC

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