Berberine alleviates myocardial diastolic dysfunction by modulating Drp1-mediated mitochondrial fission and Ca²⁺ homeostasis in a murine model of HFpEF

Abstract

Heart failure with preserved ejection fraction (HFpEF) displays normal or near-normal left ventricular ejection fraction, diastolic dysfunction, cardiac hypertrophy, and poor exercise capacity. Berberine, an isoquinoline alkaloid, possesses cardiovascular benefits. Adult male mice were assigned to chow or high-fat diet with L-NAME (“two-hit” model) for 15 weeks. Diastolic function was assessed using echocardiography and non-invasive Doppler technique. Myocardial morphology, mitochondrial ultrastructure, and cardiomyocyte mechanical properties were evaluated. Proteomics analysis, autophagic flux, and intracellular Ca²⁺ were also assessed in chow and HFpEF mice. The results show exercise intolerance and cardiac diastolic dysfunction in “two-hit”-induced HFpEF model, in which unfavorable geometric changes such as increased cell size, interstitial fibrosis, and mitochondrial swelling occurred in the myocardium. Diastolic dysfunction was indicated by the elevated E value, mitral E/A ratio, and E/e’ ratio, decreased e’ value and maximal velocity of re-lengthening (–dL/dt), and prolonged re-lengthening in HFpEF mice. The effects of these processes were alleviated by berberine. Moreover, berberine ameliorated autophagic flux, alleviated Drp1 mitochondrial localization, mitochondrial Ca²⁺ overload and fragmentation, and promoted intracellular Ca²⁺ reuptake into sarcoplasmic reticulum by regulating phospholamban and SERCA2a. Finally, berberine alleviated diastolic dysfunction in “two-hit” diet-induced HFpEF model possibly because of the promotion of autophagic flux, inhibition of mitochondrial fragmentation, and cytosolic Ca²⁺ overload.

Key words： HFpEF; berberine; Drp1; autophagy; Ca²⁺

Acknowledgements

This study was supported in part by the National Natural Science Foundation of China (Nos. 82272184 and 82130011) and Shanghai Xuhui District Scientific Research Project (Nos. 202104 and 202105). We would like to thank Drs. Yu Kong and Xu Wang (Electron Microscopy Facilities of Center for Excellence in Brain Science and Technology, Chinese Academy of Sciences, Shanghai, China) for assistance with EM sample preparation and EM image analysis.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0983-0 and is accessible for authorized users.

Compliance with ethics guidelines

Miyesaier Abudureyimu, Mingjie Yang, Xiang Wang, Xuanming Luo, Junbo Ge, Hu Peng, Yingmei Zhang, and Jun Ren declare that they have no conflict of interest. This study was approved by the Ethics Committee of Cardiovascular Department, Xuhui Central Hospital, Fudan University, Shanghai, China. Written informed consent was obtained from all individuals at admission.

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