Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation

Peng-Zhou Hang; Pei-Feng Li; Jie Liu; Feng-Feng Li; Ting-Ting Chen; Yang Pan; Man-Ru Zhang; Hua-Qing Yu; Hong-Yu Ji; Zhi-Min DU; Jing Zhao

doi:10.11909/j.issn.1671-5411.2022.11.002

Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation

J Geriatr Cardiol. 2022 Nov 28;19(11):853-866. doi: 10.11909/j.issn.1671-5411.2022.11.002.

Authors

Peng-Zhou Hang^{1

2}, Pei-Feng Li¹, Jie Liu¹, Feng-Feng Li³, Ting-Ting Chen¹, Yang Pan¹, Man-Ru Zhang², Hua-Qing Yu², Hong-Yu Ji¹, Zhi-Min DU^{1

4}, Jing Zhao^{2

5}

Affiliations

¹ Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, China.
² Department of Pharmacy, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, China.
³ Department of Pharmacology, Harbin Medical University, Harbin, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
⁵ Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.

PMID: 36561053
PMCID: PMC9748273
DOI: 10.11909/j.issn.1671-5411.2022.11.002

Abstract

Background: Pathological cardiac hypertrophy is a compensated response to various stimuli and is considered a key risk factor for heart failure. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid derivative that acts as a small-molecule brain-derived neurotrophic factor mimetic. The present study aimed to explore the potential role of 7,8-DHF in cardiac hypertrophy.

Methods: Kunming mice and H9c2 cells were exposed to transverse aortic constriction or isoproterenol (ISO) with or without 7,8-DHF, respectively. F-actin staining was performed to calculate the cell area. Transcriptional levels of hypertrophic markers, including ANP, BNP, and β-MHC, were detected. Echocardiography, hematoxylin-eosin staining, and transmission electron microscopy were used to examine the cardiac function, histology, and ultrastructure of ventricles. Protein levels of mitochondria-related factors, such as adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), were detected.

Results: 7,8-DHF inhibited compensated and decompensated cardiac hypertrophy, diminished the cross-sectional area, and alleviated the mitochondrial disorders of cardiomyocytes. Meanwhile, 7,8-DHF reduced the cell size and repressed the mRNA levels of the hypertrophic markers of ISO-treated cardiomyocytes. In addition, 7,8-DHF activated AMPK and PGC-1α signals without affecting the protein levels of mitochondrial dynamics-related molecules. The effects of 7,8-DHF were eliminanted by Compound C, an AMPK inhibitor.

Conclusions: These findings suggest that 7,8-DHF inhibited cardiac hypertrophy and mitochondrial dysfunction by activating AMPK signaling, providing a potential agent for the treatment of pathological cardiac hypertrophy.