Berberine alleviates myocardial diastolic dysfunction by modulating Drp1-mediated mitochondrial fission and Ca<sup>2+</sup> homeostasis in a murine model of HFpEF

doi:10.1007/s11684-023-0983-0

2023, Vol. 17

Issue (6) : 1219-1235 https://doi.org/10.1007/s11684-023-0983-0

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

Miyesaier Abudureyimu¹, Mingjie Yang^2,^3,^4,⁵, Xiang Wang¹, Xuanming Luo⁶, Junbo Ge^2,^3,^4,⁵(

), Hu Peng⁷(

), Yingmei Zhang^2,^3,^4,⁵(

), Jun Ren^2,^3,^4,^5,⁸(

)

¹. Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai 200031, China
². Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
³. Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai 200032, China
⁴. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
⁵. National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
⁶. Department of General Surgery, Shanghai Xuhui Central Hospital, Fudan University, Shanghai 200031, China
⁷. Department of Geriatrics, Shanghai Tenth Hospital, Tongji University, Shanghai 200072, China
⁸. Department of Medical Laboratory and Pathology, University of Washington, Seattle, WA 98195, USA

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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.

Keywords HFpEF berberine Drp1 autophagy Ca²⁺

Corresponding Author(s): Junbo Ge,Hu Peng,Yingmei Zhang,Jun Ren

Just Accepted Date: 24 April 2023 Online First Date: 31 August 2023 Issue Date: 06 February 2024

Cite this article:

Miyesaier Abudureyimu,Mingjie Yang,Xiang Wang, et al. Berberine alleviates myocardial diastolic dysfunction by modulating Drp1-mediated mitochondrial fission and Ca²⁺ homeostasis in a murine model of HFpEF[J]. Front. Med., 2023, 17(6): 1219-1235.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0983-0
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1219

Fig.1 Berberine-related pathways from PubChem database. (A, B) GO enrichment bubble plots of top ranked biological processes and cellular components in berberine-related pathways; (C) GO enrichment bar chart of top 10 ranked terms by molecular function in berberine-related pathways; and (D) GO chord plot of top 10 ranked terms by biological process in berberine-related pathways. Genes are linked to their assigned terms via colored ribbons.

Fig.2 Echocardiographic parameters of chow and HFpEF mice with or without berberine treatment. (A) Survival curve for different doses of berberine treatment. All mice treated with berberine (50 mg/kg/d, p.o.) survived after 3 weeks; (B) Illustration of experimental protocol. C57BL/6N male mice were maintained on chow or a high-fat diet (HFD, 60% of calories from fat) plus L-NAME in drinking water (0.5 g/L) for 15 weeks. Berberine was orally administered daily for the last 4 weeks in the HFpEF and chow groups; (C) Heart rate; (D) Representative images of M-mode (upper), mitral valve pulse-wave Doppler (middle), and tissue Doppler imaging (TDI, bottom); (E) LV end-diastolic diameter; (F) LV end-systolic diameter; (G) LV ejection fraction; (H) Fractional shortening; (I) Interventricular septum in diastole (d); (J) LV mass (mg); (K) Posterior wall thickness in diastole (d); (L) E wave velocity; (M) e’ wave velocity; (N) A wave velocity; (O) Mitral E/A ratio; (P) Mitral E/e' ratio. Mean ± SEM, n = 8 mice per group, *P < 0.05 vs. chow group, # P < 0.05 vs. HFpEF group.

Fig.3 General biometric parameters of chow and HFpEF mice with or without berberine treatment. (A) Representative gross images of mice; (B) Body weight; (C) Running distance; (D) Heart weight-to-tibia ratio; (E) Lung weight (wet-to-dry ratio); (F) Systolic blood pressure; (G) Diastolic blood pressure; (H) Intraperitoneal glucose tolerance test (IPGTT); (I) IPGTT area under curve; (J) Total cholesterol; (K) Total triglyceride; (L) Low-density lipoprotein; and (M) High-density lipoprotein. Mean ± SEM, n = 8 mice per group, *P < 0.05 vs. chow group, # P < 0.05 vs. HFpEF group.

Fig.4 Hematoxylin and eosin (H&E), Masson trichrome, and WGA staining images, and Western blots of markers for cardiac injury in chow and HFpEF mice with or without berberine treatment. (A) Representative gross images of mouse hearts, H&E staining, Masson staining, and WGA staining of myocardial sections; (B) Quantitative analysis of interstitial fibrosis; (C) Quantitative analysis of cardiomyocyte cross-sectional area; (D) Representative gel blots and quantitative analysis of anti-atrial natriuretic peptide (E), anti-natriuretic peptide B (F), and anti-myosin heavy chain β (G) by using specific antibodies (β-actin for loading control). Mean ± SEM, n = 6 mice per group, *P < 0.05 versus chow group, ^# P < 0.05 versus HFpEF group.

Fig.5 DHE, TUNEL staining, mitochondrial TEM ultrastructure and function, and Western blot analysis of autophagy in myocardium from chow and HFpEF mice with or without berberine treatment. (A) Representative images of myocardial DHE staining from chow and HFpEF mice with or without berberine treatment; (B) Quantitative analysis of ROS intensity in cardiomyocytes; (C) Representative images of TUNEL staining of myocardial sections from chow and HFpEF mice with or without berberine treatment; (D) Quantitative analysis of TUNEL positive cardiomyocytes; (E) Representative TEM images of mitochondria and sarcomere ultrastructure; (F–H) Quantitative analysis of major axis length, density, and perimeter of mitochondria in TEM images; (I, K–L) Representative immunoblots and quantitative analysis of pro-apoptotic proteins Bax and mitochondrial injury marker UCP2 by using specific antibodies (β-actin for loading control); (M–P) Representative immunoblots and quantitative analysis of the autophagic proteins LC3B, p62, Atg5, and Atg7 (β-actin for loading control); (J, Q–U) Representative immunoblots and quantitative analysis of mitochondrial function related proteins CS, PDH, SDH, ATPase, PGC-1α (β-actin for loading control); (V) ATP content level. Mean ± SEM, n = 6–8 mice per group, *P < 0.05 versus chow group, ^# P < 0.05 versus HFpEF group.

Fig.6 Proteomics and immunoblot analysis of mitochondrial dynamic and Ca²⁺-related proteins in myocardium from chow and HFpEF mice with or without berberine treatment. (A) Top 20 of KEGG enrichment from the proteomics of heart tissues from chow and HFpEF mice; (B) Heatmap that illustrates differentially expressed proteins from the proteomics of heart tissues from chow and HFpEF mice; (C–E) The 3D structure of binding conformation between Drp1 and berberine. Two predicted binding modalities were observed between Drp1 and berberine labeled with dotted lines; and (F–N) Representative immunoblots and quantitative analysis of Ca²⁺-related proteins, including NCX, CAMKII, SERCA2a, PLN, VDAC1, MCU, RYR1, and IP3R1 (β-actin for loading control). (O–X) Representative immunoblots and quantitative analysis of Drp1 and phosphorylation of Drp1 in total cell lysates, mitochondrial and cytoplasmic fractions (β-actin or VDAC1 for loading control); Mean ± SEM, n = 6 mice per group for proteomics and Western blot analysis, *P < 0.05 versus chow group, # P < 0.05 versus HFpEF group.

Fig.7 Cardiomyocyte contractile and diastolic and intracellular Ca²⁺ properties in chow and HFpEF mice with or without berberine treatment. (A) Illustration of contractile and diastolic properties; (B) Resting cell length; (C) Peak shortening (normalized to resting cell length); (D) Maximal velocity of shortening (dL/dt); (E) Maximal velocity of re-lengthening (–dL/dt); (F) Time-to-10%/50%/90% peak shortening (TP10/50/90); (G) Time-to-10%/50%/90% re-lengthening (TR10/50/90); (H) Illustration of intracellular Ca²⁺ properties; (I) Baseline Fura-2 fluorescent intensity (FFI); (J) Electrically-stimulated rise in FFI (ΔFFI); and (K) Intracellular Ca^{2 +} transient decay rate. Mean ± SEM, n = 20 cells from three mice per group, *P < 0.05 versus chow group, # P < 0.05 versus HFpEF group.

Fig.8 Schematic diagram illustrating proposed protective role of berberine against HFpEF. The “two-hit” insult evokes oxidative stress, intracellular Ca²⁺ overload, Drp1 phosphorylation and activation. Berberine treatment inhibits Drp1 expression and then reduces mitochondrial fission and Ca²⁺ overload, thus ameliorating cardiac diastolic dysfunction in HFpEF.

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