Fuling Yin ameliorates ventricular remodeling in heart failure rats by protecting mitochondrial homeostasis via regulation of the PGC-1α/MAPK signaling pathway_West China Medical Journal

Authors：

CHEN Min ¹ , XIAO Li ¹ , ZHANG Xiaojuan ² , TIAN Yun ³ , HUO Yuzhi ¹ , ZHANG Baocheng ⁴ ,  QIN Haizhi ¹

1. Department of Traditional Chinese Medicine, Chengdu Third People’s Hospital, Chengdu, Sichuan 610036, P. R. China;
2. Department of General Practice, Chengdu Third People’s Hospital, Chengdu, Sichuan 610036, P. R. China;
3. Department of Cardiology, Chengdu Third People’s Hospital, Chengdu, Sichuan 610036, P. R. China;
4. College of Sports Medicine and Health, Chengdu Sport University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

QIN Haizhi, Email: 1006823854@qq.com

Keywords：

Heart failure; Fuling Yin; mitochondrial homeostasis; apoptosis; peroxisome proliferator-activated receptor-gamma coactivator-1α; mitogen-activated protein kinase

DOI：

10.7507/1002-0179.202510066

Video：

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Objective To investigate the ameliorative effects of the traditional Chinese medicine formula Fuling Yin on heart failure and its potential mechanisms at the mitochondrial level. Methods Ninety SD rats were randomly divided into a blank control group (n=15) and a modeling group (n=75) using a random number table method. A chronic heart failure model was established in the modeling group by intraperitoneal injection of doxorubicin hydrochloride. One rat from the blank control group and five rats from the modeling group were randomly selected to verify the success of modeling. After confirming that the model was successfully established, the rest successfully modeled rats were randomly divided into the model group, positive drug (trimetazidine) group, and Fuling Yin low-, medium-, and high-dose groups (n=14 per group). Treatment groups were administered the respective drugs via gavage daily, while the blank control group and model group received an equal volume of pure water for 4 consecutive weeks. Cardiac function was assessed by echocardiography. Heart weight index (HWI) was calculated. Serum brain natriuretic peptide (BNP) levels and myocardial adenosine triphosphate (ATP) content were detected by enzyme-linked immunosorbent assay. Histopathological changes were observed via hematoxylin-eosin staining. Mitochondrial ultrastructure was examined using transmission electron microscopy. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening were detected by JC-1 fluorescence probe and colorimetric assay, respectively. The expression of apoptosis-related proteins, peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and key proteins of the mitogen-activated protein kinase (MAPK) signaling pathway were determined by Western Blot. Results Compared with the blank control group, the HWI and serum BNP levels in the model group were increased (P<0.01). Compared with the model group, the HWI and serum BNP levels in Fuling Yin groups were decreased (P<0.01). Pathological and ultrastructural observations showed disordered myocardial fiber arrangement, mitochondrial swelling, and cristae rupture in the model group; whereas in the Fuling Yin groups, myocardial pathological injury was alleviated, mitochondrial swelling was reduced, and membrane structure tended to be intact. Regarding mechanism indicators, compared with the model group, the myocardial ATP content increased, the red fluorescence intensity of MMP enhanced, and the mPTP opening degree decreased in the Fuling Yin groups (P<0.01). Additionally, the Bax/Bcl-2 ratio decreased, and caspase-3 protein expression was downregulated (P<0.01). Furthermore, PGC-1α protein expression was upregulated, while the expression of MAPK proteins was downregulated (P<0.01). Conclusions Fuling Yin can alleviate myocardial injury and delay ventricular remodeling in doxorubicin-induced heart failure rats. Its mechanism may be related to regulating the PGC-1α/MAPK signaling pathway to maintain mitochondrial homeostasis, thereby inhibiting mitochondria-mediated cardiomyocyte apoptosis.

Citation： CHEN Min, XIAO Li, ZHANG Xiaojuan, TIAN Yun, HUO Yuzhi, ZHANG Baocheng, QIN Haizhi. Fuling Yin ameliorates ventricular remodeling in heart failure rats by protecting mitochondrial homeostasis via regulation of the PGC-1α/MAPK signaling pathway. West China Medical Journal, 2025, 40(12): 1956-1964. doi: 10.7507/1002-0179.202510066 Copy

1.	Zeng Y, Yang S, Yu X, et al. A multimodal parallel method for left ventricular dysfunction identification based on phonocardiogram and electrocardiogram signals synchronous analysis. Math Biosci Eng, 2022, 19(9): 9612-9635.
2.	Molinsky RL, Shah A, Yuzefpolskaya M, et al. Infection-related hospitalization and incident heart failure: the atherosclerosis risk in communities study. J Am Heart Assoc, 2025, 14(3): e033877.
3.	Nguyen DV, Le TN, Truong BQ, et al. Efficacy and safety of angiotensin receptor-neprilysin inhibition in heart failure patients with end-stage kidney disease on maintenance dialysis: a systematic review and meta-analysis. Eur J Heart Fail, 2025, 27(1): 72-84.
4.	Jiang D, Wang J, Wang R, et al. Comprehensive insights into mechanisms for ventricular remodeling in right heart failure. Rev Cardiovasc Med, 2024, 25(12): 426.
5.	Zhang L, He J, Wang J, et al. Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy. Cell Death Dis, 2021, 12(5): 470.
6.	Ke Y, Lei M, Wang X, et al. Novel roles of PAK1 in the heart. Cell Logist, 2012, 2(2): 89-94.
7.	Piquereau J, Boitard SE, Ventura-Clapier R, et al. Metabolic therapy of heart failure: is there a future for B vitamins?. Int J Mol Sci, 2021, 23(1): 30.
8.	Gao X, Zhang X, Hu J, et al. Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria-mediated pathway. Mol Med Rep, 2018, 17(1): 284-292.
9.	Qian K, Tang J, Ling YJ, et al. Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. EBioMedicine, 2023, 98: 104863.
10.	Song X, Qu H, Yang Z, et al. Efficacy and safety of l-carnitine treatment for chronic heart failure: a meta-analysis of randomized controlled trials. Biomed Res Int, 2017, 2017: 6274854.
11.	Liu CJ, Wang LK, Tsai FM. The application and molecular mechanisms of mitochondria-targeted antioxidants in chemotherapy-induced cardiac injury. Curr Issues Mol Biol, 2025, 47(3): 176.
12.	Zhong Z, Hou Y, Zhou C, et al. FL3 mitigates cardiac ischemia-reperfusion injury by promoting mitochondrial fusion to restore calcium homeostasis. Cell Death Discov, 2025, 11(1): 304.
13.	高廣飛. 基于黃煌“方-病-人”思想運用外臺茯苓飲體會. 山西中醫, 2023, 39(9): 69-70.
14.	許永波. 小半夏湯聯合外臺茯苓飲對右心功能不全患者的療效分析. 中西醫結合心血管病電子雜志, 2023, 11(4): 39-41.
15.	張胤, 楊祥坤. 楊祥坤教授治療心悸的臨床經驗. 光明中醫, 2018, 33(5): 721-723.
16.	Zhang Y, Huang J, Sun M, et al. Preparation, characterization, antioxidant and antianemia activities of Poria cocos polysaccharide iron (III) complex. Heliyon, 2023, 9(1): e12819.
17.	Roh JD, Houstis N, Yu A, et al. Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice. Aging Cell, 2020, 19(6): e13159.
18.	Pandey KN. Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation. Can J Physiol Pharmacol, 2011, 89(8): 557-573.
19.	Wu ZL, Ren H, Lai WY, et al. Sclederma of Poria cocos exerts its diuretic effect via suppression of renal aquaporin-2 expression in rats with chronic heart failure. J Ethnopharmacol, 2014, 155(1): 563-571.
20.	Zhou Z, Li M, Zhang Z, et al. Overview of Panax ginseng and its active ingredients protective mechanism on cardiovascular diseases. J Ethnopharmacol, 2024, 334: 118506.
21.	Wan S, Cui Z, Wu L, et al. Ginsenoside Rd promotes omentin secretion in adipose through TBK1-AMPK to improve mitochondrial biogenesis via WNT5A/Ca²⁺ pathways in heart failure. Redox Biol, 2023, 60: 102610.
22.	Shi Y, Liu C, Xiong S, et al. Ling-Gui-Qi-Hua formula alleviates left ventricular myocardial fibrosis in rats with heart failure with preserved ejection fraction by blocking the transforming growth factor-β1 /Smads signaling pathway. J Ethnopharmacol, 2023, 317: 116849.
23.	Sunagawa Y, Iwashimizu S, Ono M, et al. The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis. J Pharmacol Sci, 2025, 158(2): 84-94.
24.	Xu GR, Zhang C, Yang HX, et al. Modified citrus pectin ameliorates myocardial fibrosis and inflammation via suppressing galectin-3 and TLR4/MyD88/NF-κB signaling pathway. Biomed Pharmacother, 2020, 126: 110071.
25.	Kawase Y, Sunagawa Y, Shimizu K, et al. 6-Shogaol, an active component of ginger, inhibits p300 histone acetyltransferase activity and attenuates the development of pressure-overload-induced heart failure. Nutrients, 2023, 15(9): 2232.
26.	Sivapackiam J, Sharma M, Schindler TH, et al. PET Radiopharmaceuticals for Imaging Chemotherapy-Induced Cardiotoxicity. Curr Cardiol Rep, 2020, 22(8): 62.
27.	Lu Y, Li F, Wu Q, et al. A bibliometric and visualized analysis of research on mitochondria in myocardial ischemia from 2015 to 2024. Front Cardiovasc Med, 2025, 12: 1547604.
28.	Li W, Zhu L, Chen Y, et al. Association between mitochondrial DNA levels and depression: a systematic review and meta-analysis. BMC Psychiatry, 2023, 23(1): 866.
29.	Liu Z, Gao Z, Zeng L, et al. Nobiletin ameliorates cardiac impairment and alleviates cardiac remodeling after acute myocardial infarction in rats via JNK regulation. Pharmacol Res Perspect, 2021, 9(2): e00728.
30.	Schwarze SR, Lin EW, Christian PA, et al. Intracellular death platform steps-in: targeting prostate tumors via endoplasmic reticulum (ER) apoptosis. Prostate, 2008, 68(15): 1615-1623.
31.	Yuan S, Pan Y, Xu T, et al. Daurisoline inhibits ESCC by inducing G1 cell cycle arrest and activating er stress to trigger noxa-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptosis via p-eIF2 α-ATF4 axis. Oxid Med Cell Longev, 2022, 2022: 5382263.
32.	Sang P, Ma Y, Zhang X, et al. BMAL1 attenuates intervertebral disc degeneration by activating the SIRT1/PGC-1α pathway: evidence from vitro studies. Sci Rep, 2025, 15(1): 9651.
33.	Sandroni PB, Fisher-Wellman KH, Jensen BC. Adrenergic receptor regulation of mitochondrial function in cardiomyocytes. J Cardiovasc Pharmacol, 2022, 80(3): 364-377.
34.	Sihag S, Cresci S, Li AY, et al. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. J Mol Cell Cardiol, 2009, 46(2): 201-212.
35.	Wang L, Zhang TP, Zhang Y, et al. Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein. Sci Rep, 2016, 6: 28399.

1. Zeng Y, Yang S, Yu X, et al. A multimodal parallel method for left ventricular dysfunction identification based on phonocardiogram and electrocardiogram signals synchronous analysis. Math Biosci Eng, 2022, 19(9): 9612-9635.
2. Molinsky RL, Shah A, Yuzefpolskaya M, et al. Infection-related hospitalization and incident heart failure: the atherosclerosis risk in communities study. J Am Heart Assoc, 2025, 14(3): e033877.
3. Nguyen DV, Le TN, Truong BQ, et al. Efficacy and safety of angiotensin receptor-neprilysin inhibition in heart failure patients with end-stage kidney disease on maintenance dialysis: a systematic review and meta-analysis. Eur J Heart Fail, 2025, 27(1): 72-84.
4. Jiang D, Wang J, Wang R, et al. Comprehensive insights into mechanisms for ventricular remodeling in right heart failure. Rev Cardiovasc Med, 2024, 25(12): 426.
5. Zhang L, He J, Wang J, et al. Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy. Cell Death Dis, 2021, 12(5): 470.
6. Ke Y, Lei M, Wang X, et al. Novel roles of PAK1 in the heart. Cell Logist, 2012, 2(2): 89-94.
7. Piquereau J, Boitard SE, Ventura-Clapier R, et al. Metabolic therapy of heart failure: is there a future for B vitamins?. Int J Mol Sci, 2021, 23(1): 30.
8. Gao X, Zhang X, Hu J, et al. Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria-mediated pathway. Mol Med Rep, 2018, 17(1): 284-292.
9. Qian K, Tang J, Ling YJ, et al. Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. EBioMedicine, 2023, 98: 104863.
10. Song X, Qu H, Yang Z, et al. Efficacy and safety of l-carnitine treatment for chronic heart failure: a meta-analysis of randomized controlled trials. Biomed Res Int, 2017, 2017: 6274854.
11. Liu CJ, Wang LK, Tsai FM. The application and molecular mechanisms of mitochondria-targeted antioxidants in chemotherapy-induced cardiac injury. Curr Issues Mol Biol, 2025, 47(3): 176.
12. Zhong Z, Hou Y, Zhou C, et al. FL3 mitigates cardiac ischemia-reperfusion injury by promoting mitochondrial fusion to restore calcium homeostasis. Cell Death Discov, 2025, 11(1): 304.
13. 高廣飛. 基于黃煌“方-病-人”思想運用外臺茯苓飲體會. 山西中醫, 2023, 39(9): 69-70.
14. 許永波. 小半夏湯聯合外臺茯苓飲對右心功能不全患者的療效分析. 中西醫結合心血管病電子雜志, 2023, 11(4): 39-41.
15. 張胤, 楊祥坤. 楊祥坤教授治療心悸的臨床經驗. 光明中醫, 2018, 33(5): 721-723.
16. Zhang Y, Huang J, Sun M, et al. Preparation, characterization, antioxidant and antianemia activities of Poria cocos polysaccharide iron (III) complex. Heliyon, 2023, 9(1): e12819.
17. Roh JD, Houstis N, Yu A, et al. Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice. Aging Cell, 2020, 19(6): e13159.
18. Pandey KN. Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation. Can J Physiol Pharmacol, 2011, 89(8): 557-573.
19. Wu ZL, Ren H, Lai WY, et al. Sclederma of Poria cocos exerts its diuretic effect via suppression of renal aquaporin-2 expression in rats with chronic heart failure. J Ethnopharmacol, 2014, 155(1): 563-571.
20. Zhou Z, Li M, Zhang Z, et al. Overview of Panax ginseng and its active ingredients protective mechanism on cardiovascular diseases. J Ethnopharmacol, 2024, 334: 118506.
21. Wan S, Cui Z, Wu L, et al. Ginsenoside Rd promotes omentin secretion in adipose through TBK1-AMPK to improve mitochondrial biogenesis via WNT5A/Ca²⁺ pathways in heart failure. Redox Biol, 2023, 60: 102610.
22. Shi Y, Liu C, Xiong S, et al. Ling-Gui-Qi-Hua formula alleviates left ventricular myocardial fibrosis in rats with heart failure with preserved ejection fraction by blocking the transforming growth factor-β1 /Smads signaling pathway. J Ethnopharmacol, 2023, 317: 116849.
23. Sunagawa Y, Iwashimizu S, Ono M, et al. The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis. J Pharmacol Sci, 2025, 158(2): 84-94.
24. Xu GR, Zhang C, Yang HX, et al. Modified citrus pectin ameliorates myocardial fibrosis and inflammation via suppressing galectin-3 and TLR4/MyD88/NF-κB signaling pathway. Biomed Pharmacother, 2020, 126: 110071.
25. Kawase Y, Sunagawa Y, Shimizu K, et al. 6-Shogaol, an active component of ginger, inhibits p300 histone acetyltransferase activity and attenuates the development of pressure-overload-induced heart failure. Nutrients, 2023, 15(9): 2232.
26. Sivapackiam J, Sharma M, Schindler TH, et al. PET Radiopharmaceuticals for Imaging Chemotherapy-Induced Cardiotoxicity. Curr Cardiol Rep, 2020, 22(8): 62.
27. Lu Y, Li F, Wu Q, et al. A bibliometric and visualized analysis of research on mitochondria in myocardial ischemia from 2015 to 2024. Front Cardiovasc Med, 2025, 12: 1547604.
28. Li W, Zhu L, Chen Y, et al. Association between mitochondrial DNA levels and depression: a systematic review and meta-analysis. BMC Psychiatry, 2023, 23(1): 866.
29. Liu Z, Gao Z, Zeng L, et al. Nobiletin ameliorates cardiac impairment and alleviates cardiac remodeling after acute myocardial infarction in rats via JNK regulation. Pharmacol Res Perspect, 2021, 9(2): e00728.
30. Schwarze SR, Lin EW, Christian PA, et al. Intracellular death platform steps-in: targeting prostate tumors via endoplasmic reticulum (ER) apoptosis. Prostate, 2008, 68(15): 1615-1623.
31. Yuan S, Pan Y, Xu T, et al. Daurisoline inhibits ESCC by inducing G1 cell cycle arrest and activating er stress to trigger noxa-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptosis via p-eIF2 α-ATF4 axis. Oxid Med Cell Longev, 2022, 2022: 5382263.
32. Sang P, Ma Y, Zhang X, et al. BMAL1 attenuates intervertebral disc degeneration by activating the SIRT1/PGC-1α pathway: evidence from vitro studies. Sci Rep, 2025, 15(1): 9651.
33. Sandroni PB, Fisher-Wellman KH, Jensen BC. Adrenergic receptor regulation of mitochondrial function in cardiomyocytes. J Cardiovasc Pharmacol, 2022, 80(3): 364-377.
34. Sihag S, Cresci S, Li AY, et al. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. J Mol Cell Cardiol, 2009, 46(2): 201-212.
35. Wang L, Zhang TP, Zhang Y, et al. Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein. Sci Rep, 2016, 6: 28399.

West China Medical Journal

Fuling Yin ameliorates ventricular remodeling in heart failure rats by protecting mitochondrial homeostasis via regulation of the PGC-1α/MAPK signaling pathway

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