Cardiovascular Diabetology
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2025
·Vol. 25
·期 1
·5
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IF 10.6
Jia Yumeng,Niu Wenhui,Liu Lu,Zhang Qun,Li Dingwei,Dai Tangyu,Du Jie,Wang Lei
Background Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. In addition to its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate–GPR91 signaling in HFpEF pathogenesis remain incompletely understood. Methods HFpEF models were established in wild-type (WT), global GPR91 knockout (Gpr91 -/- ), and cardiomyocyte-specific GPR91 knockout (Gpr91 ΔCM ) mice, with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify pathways regulated by succinate–GPR91 signaling. Mechanistic studies in human AC16 cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Additionally, rescue experiments were performed to confirm the functional relevance of succinate–GPR91 signaling in cardiomyocyte metabolism and HFpEF progression. Results Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in WT HFpEF mice, whereas these protective effects were abolished in both Gpr91 -/- and Gpr91 ΔCM mice. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose–lipid metabolism and NAD + biosynthesis in Gpr91 fl/fl but not in Gpr91 ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD + production via Gq-mediated signaling, thereby promoting cardiomyocyte metabolic reprogramming. Conclusion These findings identify the succinate–GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF. Graphical
研究领域:
心脏病学
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分子生物学
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代谢学
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信号转导
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内分泌学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Yuexin Yu,Yaping Xu,Jinfu Chen,Yao Yao,Yingtian Liu,Tan Huang,Shaolong Yang,King-Hwa Ling,Jacques P. Guyette,Bakiah Shaharuddin,Zhikun Guo,Jun Jie Tan
BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is associated with substantial morbidity and mortality. Although sodium–glucose cotransporter-2 inhibitors (SGLT2is) have shown efficacy in reducing HFpEF hospitalizations, the disease’s multi-pathway pathogenesis often limits the effectiveness of single-target interventions. This study examines whether the cardiovascular benefits of empagliflozin (EMPA) can be synergistically enhanced by co-administration with the targeted anti-fibrotic agent pirfenidone (PFD).AimsWe hypothesized that simultaneous modulation of metabolic stress and pro-fibrotic signaling would lead to synergistic structural and functional recovery in a severe HFpEF phenotype.MethodsHFpEF was induced in Sprague–Dawley rats (n = 16/group) using a two-hit model [NG-nitro-L-arginine methyl ester (L-NAME) and a high-fat diet (HFD)] over 5 weeks. The rats subsequently received daily oral EMPA (0.35 g/kg/d), PFD (0.3 g/kg/d), or combination therapy (EMPA + PFD) for 4 weeks. Treatment efficacy was evaluated via echocardiography, histopathology, and exercise tolerance testing. Further insights into the underlying transcriptional mechanisms were gained through RNA sequencing and semi-quantitative Western blotting. Bliss independence analysis was used to analyze pharmacological synergy.ResultsCo-treatment with EMPA + PFD significantly enhanced diastolic indices, left ventricular ejection fraction (LVEF), fractional shortening (FS), and cardiac output (CO) compared with controls and monotherapy groups (p < 0.05). Histological analysis revealed reduced cardiomyocyte hypertrophy and lower collagen deposition, particularly in the endocardium. Although additive improvement in systemic hemodynamics was observed, EMPA + PFD co-treatment exerted compartmentalized synergy within the myocardium. The combination reversed cellular hypertrophy and deep fibrosis, restoring diastolic and systolic function (p < 0.05). Transcriptomic profiling revealed that local myocardial rescue was mediated by gene networks linked to protein kinase C-activating G-protein-coupled receptor signaling, which blocked the downstream PKC/NF-κB inflammatory pathway and transforming growth factor-beta (TGF-β)-driven fibrosis, thereby explaining the molecular basis of functional improvement.ConclusionDual therapy with EMPA and PFD achieves compartmentalized synergy, effectively eliminating cellular hypertrophy and deep fibrosis, thereby restoring cardiac mechanics. These findings provide mechanistic proof of concept that multi-axis metabolic and antifibrotic combinations can disrupt the complex pathological cycle of HFpEF.
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
·
IF 5.1
Qian Chen,Huaxing Zhang,Yuhong Chen,Yangxuan Peng,Yuhan Yao,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xu Teng,Mingqi Zheng,Bing Xiao,Yuming Wu,Sheng Jin
Aims The present study aimed to investigate the direct link between trimethylamine N-oxide (TMAO) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Materials and methods Diastolic dysfunction is the main manifestation of HFpEF, so the “two-hit” mouse HFpEF model are used. After treated with high-fat diet (HFD) and N [w] -nitro-l-arginine methyl ester (L-NAME) for 8 weeks, the cardiac function, myocardial fibrosis, oxidative stress levels, and molecular alterations were assessed. Key findings The HFpEF mice displayed a declined diastolic function, characterized by an increase in the E/E' ratio, accompanied by a significant increase in plasma brain natriuretic peptide levels and cardiac fibrosis and down-regulation of SERCA2 expression, while, DMB treatment improved diastolic function. Subsequently, TMAO was injected intraperitoneally into the mice for 1 month and found that TMAO induced diastolic dysfunction. In addition, we found that either the HFD and L-NAME or TMAO treatment down-regulated Piezo1 expression, and the cardiomyocyte-specific Piezo1 knockout mice (Piezo1 ΔCM ) also had diastolic dysfunction. Moreover, the NOX4 expression was up-regulated and the reactive oxygen species levels were increased in the heart tissues of Piezo1 ΔCM or TMAO-treated mice, which was reversed by a Piezo1 activator (Yoda1) in the TMAO-treated mice. Yoda1 also reversed diastolic dysfunction in the HFpEF mice. Significance In conclusion, our data revealed that TMAO-induced oxidative stress injury by down-regulating Piezo1 to be involve in cardiac diastolic dysfunction of HFpEF. It should be noted that this preclinical study did not evaluate HFpEF-related symptoms such as exercise intolerance or pulmonary congestion, which warrant further validation.
研究领域:
心脏病学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
·
IF 6.3
Zijun Cao,Jinfeng Duan,Shan Meng,Zijun Zhou,Yuting Huang,Xin Chen,Jikai Zhao,Tao Huang,Guoxin Zhang,Tong Su,Liming Yu,Zongtao Yin,Huishan Wang
Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently coexist due to shared risk factors, yet optimal therapeutic interventions remain elusive. Berberine (BBR), a widely used isoquinoline alkaloid, has demonstrated potential anti-arrhythmic properties. However, its specific effects and regulatory mechanisms in HFpEF-related AF are not fully understood. The present study was designed to clarify the pathological characteristics of HFpEF-associated AF and further evaluate the therapeutic effects of BBR. In this study, we developed a high-fat diet plus Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced murine HFpEF model to investigate the impact of berberine on the pathogenesis of HFpEF-associated AF. Bioinformatics and in vivo analyses revealed a progressive increase in atrial endoplasmic reticulum (ER) stress and lipid metabolic dysregulation. The HFpEF model exhibited significant atrial structural and electrical remodeling, which was dose-dependently reversed by berberine treatment. Further investigation showed that berberine effectively preserved atrial lipid metabolism, reduced ER stress and atrial inflammation, and restored atrial AMP-activated protein kinase (AMPK) activity. These protective effects were abolished by Compound C treatment, yet replicated by metformin or 4-phenylbutyric acid administration. Notably, the beneficial effects of berberine were validated in an isoprenaline/palmitic acid (ISO/PA)-treated HL-1 cell model. Our study highlights the therapeutic potential of berberine in mitigating HFpEF-associated atrial ER stress, lipid accumulation, and inflammatory responses. By targeting and preserving atrial AMPK signaling, berberine offers a promising therapeutic approach to combat HFpEF-associated AF.
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
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IF 6.9
Han Yan-lu,Yan Teng-teng,Li Hua-xin,Chen Sha-sha,Zhang Zhen-zhen,Wang Meng-yao,Chen Mei-jie,Chen Yuan-li,Yang Xiao-xiao,Wei Ling-ling,Duan Ya-jun,Zhang Shuang
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L -NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H 2 O 2 -induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Jiahui Chen,Liping Zhang,Ting Xie,Xiao Zhang,Congcong Pan,Fangli Sun,Wenfeng Li,Zhijie Sun,Deli Dong
The clinical antiprotozoal drug nitazoxanide has been demonstrated to improve the experimental diabetes mellitus, lipid metabolism disorders, atherosclerosis and inhibit inflammation. Since the pathogenesis of heart failure with preserved ejection (HFpEF) is multifactorial and closely associated with the aforementioned diseases, we aim to study the effect of nitazoxanide on high-fat diet (HFD) plus L-NAME (N ω -nitro-L-arginine methyl ester)-induced HFpEF and metabolic syndrome in mice. We found that oral nitazoxanide improved cardiac hypertrophy, cardiac fibrosis, cardiac diastolic dysfunction, increased blood pressure, impaired exercise tolerance, impaired glucose handling, serum lipid disorders, hepatic steatosis, increased weight of white adipose tissues and kidney fibrosis in HFD+L-NAME-treated mice. In the established HFD+L-NAME-induced HFpEF and metabolic syndrome mouse model, therapeutic treatment with nitazoxanide rescued HFD+L-NAME-induced pathological phenotypes as mentioned above. The in vitro experiments revealed that tizoxanide, the active metabolite of nitazoxanide, increased the basal mitochondria metabolism of cardiomyocytes, inhibited cardiomyocyte hypertrophy and collagen secretion from cardiac fibroblasts, and relaxed phenylephrine- and U46619-induced constriction of rat mesenteric arteries, indicating that the direct effect of tizoxanide might partly contribute to the protective effect of nitazoxanide against HFpEF in vivo . The present study suggests that nitazoxanide might be a potential drug for HFpEF and metabolic syndrome therapy.
研究领域:
心脏病学
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药理学
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代谢性疾病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of the American Heart Association
·
2022
·
IF 6.106
Xin‐Lin Zhang,Ting‐Yu Wang,Zheng Chen,Hong‐Wei Wang,Yong Yin,Lian Wang,Yong Wang,Biao Xu,Wei Xu
BackgroundHeart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown.Methods and ResultsSerum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice.ConclusionsNETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
研究领域:
心脏病学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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