Qishen Granule Modulates Metabolism Flexibility Against Myocardial Infarction via HIF-1α-Dependent Mechanisms in Rats

Abstract

Ethnopharmacological relevance: Qishen granule (QSG) is a traditional Chinese medicine formulation that has a long history of use in the treatment of cardiovascular diseases and have demonstrated excellent clinical efficacy. QSG has been shown to regulate fatty acid and glucose metabolism in the treatment of heart failure. However, the exact mechanism has not yet been revealed.Aim of the study: The aim of this study was to assess the cardio-protection and effects of substrate utilization of Qishen granule (QSG) on heart failure rats.Materials and methods:  Echocardiography, positron emission tomography (PET), hematological and biochemical analyses, and histological examination were used to assess the cardio-protection and effects of substrate utilization of Qishen granule (QSG) on left anterior descending (LAD) ligation-induced HF in rats. In vitro, hypoxia-induced H9C2 model was established to investigate the effects of QSG on energy metabolism.Results: QSG improved cardiac function, promoting glucose metabolism in the border area and lipid metabolism in remote area of the hearts of HF rats. In vitro, QSG modulated the HIF-1α pathway to regulate glucose and lipid substrate utilization in cardiomyocytes. Specifically, QSG promoted HIF-1α expression and entry into the nucleus at high levels of hypoxia, thereby promoting increased compensatory glucose metabolism, while reducing nuclear accumulation of HIF-1α at relatively low levels of hypoxia, protecting against increased lipid metabolism.Conclusion: QSG regulated metabolic flexibility against acute myocardial infarction via HIF-1α-dependent mechanisms. providing a promising novel approach for HIF-1α as a regulatory target of energy metabolism for the treatment of HF.

Note:
Funding declaration: This work was financially supported, in part, by the Grants from the National Natural Science Foundation of China (No. 81673802, and 82174215), National Science Fund for Excellent Young Scholars (No.82222075), National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2019ZX09201004-001-011).

Conflict of Interests: The authors have no relevant financial or nonfinancial interests to disclose.

Ethical Approval: Our study followed the Guide for the Care and Use of Laboratory Animals established by the US National Institutes of Health (NIH publication No. 85-23, revised 1996), and Beijing University of Chinese Medicine Animal Care Committee (approve code BUCM-4-2021042701-2033).

Keywords: Qishen granule, substrate utilization, HIF-1α pathway, energy metabolism, heart failure