LIFE SCIENCES
·
2025
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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
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
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IF 10.273
Yuejun Yao,Jie Ding,Zhaoyi Wang,Haolan Zhang,Jieqi Xie,Yingchao Wang,Liangjie Hong,Zhengwei Mao,Jianqing Gao,Changyou Gao
Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous diseases including atherosclerosis, diabetes, inflammation and myocardial infarction (MI). In this study, a ROS-responsive biodegradable elastomeric polyurethane containing thioketal (PUTK) linkages was synthesized from polycaprolactone diol (PCL-diol ), 1,6-hexamethylene diisocyanate (HDI), and ROS-cleavable chain extender . The PUTK was electrospun into fibrous patches with the option to load glucocorticoid methylprednisolone (MP), which were then used to treat MI of rats in vivo . The fibrous patches exhibited suitable mechanical properties and high elasticity. The molecular weight of PUTK was decreased significantly after incubation in 1 mM H 2 O 2 solution for 2 weeks due to the degradation of thioketal bonds on the polymer backbone . Both the PUTK and PUTK/MP fibrous patches showed good antioxidant property in an oxidative environment in vitro . Implantation of the ROS-responsive polyurethane patches in MI of rats in vivo could better protect cardiomyocytes from death in the earlier stage (24 h) than the non ROS-responsive ones. Implantation of the PUTK/MP fibrous patches for 28 days could effectively improve the reconstruction of cardiac functions including increased ejection fraction , decreased infarction size, and enhanced revascularization of the infarct myocardium.
研究领域:
生物材料
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心脏病学
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药理学
✓ 已验证
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
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产品关联
DOI
PubMed
高影响因子
Journal of Cardiovascular Translational Research
·
2022
·Vol. 16
·期 1
·127-140
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IF 3.216
Hao Jiameng,Chang Liping,Wang Dandong,Ji Chuanyuan,Zhang Shaolan,Hou Yunlong,Wu Yiling
Heart failure with preserved ejection fraction (HFpEF) is a common public health problem associated with increased morbidity and long-term mortality. However, effective treatment for HFpEF was not discovered yet. In the present study, we aimed to decipher the effects of Periplocin on DOCA-induced heart failure rats and explore the possible underlying mechanisms. We demonstrated that Periplocin could significantly attenuate cardiac structural remodeling and improve cardiac diastolic function. Of note, Periplocin significantly inhibited the recruitment of inflammatory and immune cells and decreased the expression of serum inflammatory cytokines. Meanwhile, Periplocin had the effect of cardiac glycosides to improve cardiomyocyte contractility and calcium transient amplitude. These findings indicate that Periplocin might be a potential medicine to treat HFpEF in patients. Graphical abstract
研究领域:
心脏病学
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药理学
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炎症
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-14
·
IF 14.7
Xue Fangchao,Zhao Shanlan,Tian Hao,Qin Haoxiang,Li Xiaochen,Jian Zhao,Du Jiahui,Li Yanzhao,Wang Yanhong,Lin Lin,Liu Chen,Shang Yongning,He Lang,Xing Malcolm,Zeng Wen
During myocardial infarction, microcirculation disturbance in the ischemic area can cause necrosis and formation of fibrotic tissue, potentially leading to malignant arrhythmia and myocardial remodeling. Here, we report a microchanneled hydrogel suture for two-way signal communication, pumping drugs on demand, and cardiac repair. After myocardial infarction, our hydrogel suture monitors abnormal electrocardiogram through the mobile device and triggers nitric oxide on demand via the hydrogel sutures’ microchannels, thereby inhibiting inflammation, promoting microvascular remodeling, and improving the left ventricular ejection fraction in rats and minipigs by more than 60% and 50%, respectively. This work proposes a suture for bidirectional communication that acts as a cardio-patch to repair myocardial infarction, that remotely monitors the heart, and can deliver drugs on demand.
研究领域:
心脏病学
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生物医学工程
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组织工程
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药物递送系统
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医疗器械
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Lu Bai,Jing Dai,Yuxuan Xia,Kaichuan He,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xiangjian Zhang,Xu Teng,Yuming Wu,Sheng Jin
Although it is an essential nutrient, high choline intake directly or indirectly via its metabolite is associated with increased risk of cardiovascular disease, the mechanism of which remains to be elucidated. The present study was performed to investigate whether hydrogen sulfide (H2S) was involved in high choline-induced cardiac dysfunction and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS), the indicators of cardiac function measured by echocardiography, were significantly decreased in mice fed a diet containing 1.3% choline for 4 months as compared to the control, while applying 3,3-dimethyl-1-butanol (DMB) to suppress trimethylamine N-oxide (TMAO, a metabolite of choline) generation ameliorated the cardiac function. Subsequently, we found that feeding choline or TMAO significantly increased the protein levels of cyclic GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon genes (STING), NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β) as compared to the control, which indicated the activation of cGAS-STING-NLRP3 inflammasome axis. Moreover, the protein expression of cystathionine γ-lyase (CSE), the main enzyme for H2S production in the cardiovascular system, was significantly increased after dietary supplementation with choline, but the plasma H2S levels were significantly decreased. To observe the effect of endogenous H2S, CSE knockout (KO) mice were used, and we found that the EF, FS, and plasma H2S levels in WT mice were significantly decreased after dietary supplementation with choline, while there was no difference between CSE KO + control and CSE KO + choline group. To observe the effect of exogenous H2S, mice were intraperitoneally injected with sodium hydrosulfide (NaHS, a H2S donor) for 4 months, and we found that NaHS improved the cardiac function and reduced the protein levels of cGAS, STING, NLRP3, caspase-1, and IL-1β in mice receiving dietary choline. In conclusion, our studies revealed that high choline diet decreased plasma H2S levels and induced cardiac dysfunction via cGAS-STING-NLRP3 inflammasome axis while H2S treatment could restore the cardiac function by inhibiting cGAS-STING-NLRP3 inflammasome axis.
研究领域:
心脏病学
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营养学
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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
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Tianhu Wang,Yabin Wang,Yingjie Zhang,Zhiyi Fang,Sulei Li,Zhenghui Gu,Yan Ma,Linghuan Wang,Dong Han,Changyong Wang,Jin Zhou,Feng Cao
In this study, we synthesized mesoporous polydopamine nanoparticles (MPDA NPs) using an emulsion-induced interface assembly strategy and loaded epigallocatechin gallate (EGCG) into MPDA NPs via electrostatic attraction to form EGCG@MPDA NPs. In the post myocardial infarction (MI) environment, these interventions specifically aimed to eliminate reactive oxygen species (ROS) and facilitate the repair of MI. We further combined them with a thermosensitive chitosan (CS) hydrogel to construct an injectable composite hydrogel (EGCG@MPDA/CS hydrogel). Utilizing in vitro experiments, the EGCG@MPDA/CS hydrogel exhibited excellent ROS-scavenging ability of H9C2 cells under the oxidative stress environment and also could inhibit their apoptosis. The EGCG@MPDA/CS hydrogel significantly promoted left ventricular ejection fraction (LVEF) in infarcted rat models post injection for 28 days compared to the PBS group (51.25 ± 1.73% vs 29.31 ± 0.78%, P < 0.05). In comparison to the PBS group, histological analysis revealed a substantial increase in left ventricular (LV) wall thickness in the EGCG@MPDA/CS hydrogel group (from 0.58 ± 0.03 to 1.39 ± 1.11 mm, P < 0.05). This work presents a novel approach to enhance MI repair by employing the EGCG@MPDA/CS hydrogel. This hydrogel effectively reduces local oxidative stress by ROS and stimulates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.
研究领域:
纳米技术
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心脏病学
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生物材料
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Shuoji Zhu,Changjiang Yu,Nanbo Liu,Mingyi Zhao,Zerui Chen,Jian Liu,Ge Li,Huanlei Huang,Huiming Guo,Tucheng Sun,Jimei Chen,Jian Zhuang,Ping Zhu
Umbilical cord mesenchymal stem cells (UCMSCs) transplantation has been proposed as a promising treatment modality for myocardial infarction (MI), but the low retention rate remains a considerable challenge. Injectable natural polymer hydrogels with conductivity ability are highly desirable as cell delivery vehicles to repair infarct myocardium and restore the cardiac function. In this work, we developed a hydrogel system based on gelatin methacrylate (GelMA) and oxidized dextran (ODEX) as cell delivery vehicles for MI. And dopamine could be used as a reductant of graphene oxide (GO) to form reductive GO (rGO). By adjusting the amount of rGO, the conductivity of hydrogels with 0.5 mg/mL rGO concentration (≈10 −4 S/cm) was similar to that of natural heart tissue. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell delivery ability of UCMSCs. More importantly, GelMA-O5/rGO hydrogel could promote UCMSCs growth and proliferation, improve the myocardial differentiation ability of UCMSCs, and up-regulate the expression of cTnI and Cx43. Further in vivo experiments demonstrated that GelMA-O5/rGO/UCMSCs Hydrogel could significantly improve the ejection fraction (EF) of rats and significantly reduce myocardial infarct area compared to PBS group, promote the survival of UCMSCs, enhance the expression level of cTnI and Cx43, and decrease the expression level of caspase-3. The findings of this study suggested that the injectable conductive GelMA-O5/rGO hydrogel encapsulating UCMSCs could improve damaged myocardial tissue and reconstruct myocardial function, which will be a promising therapeutic strategy for cardiac repair.
研究领域:
生物材料
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干细胞治疗
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心脏病学
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组织工程
✓ 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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Zetao Heng,Min Hong,Zhaocai Zhang,Ximing Ye,Jianan Zhou,Wentao Wu,Jiabing Rong,Yinchuan Xu
Heart failure with preserved ejection fraction (HFpEF) is a prevalent complex syndrome characterized by diastolic dysfunction with limited therapeutic options. While the renin-angiotensin system (RAS) is implicated in heart failure pathogenesis, the causal contribution of angiotensinogen (AGT), the unique precursor of the RAS, to HFpEF remains undefined. Using a two-hits mouse HFpEF model (high-fat diet + L-NAME), consistent upregulation of hepatic and plasma AGT is identified in wild-type mice of both sexes. Critically, hepatocyte-specific AGT deletion directly ameliorated diastolic dysfunction in male and female HFpEF mice, whereas systemic angiotensin II blockade (losartan) failed to improve cardiac diastolic function. Mechanistically, hepatic AGT drove HFpEF through LRP2-mediated internalization in cardiac endothelial cells, suppressing the GATA2/Pim3 signaling axis, which inhibited microvascular angiogenesis and ultimately exacerbated diastolic dysfunction. To validate therapeutic potential, it is demonstrated that 18β-glycyrrhetinic acid – identified as a potent hepatic AGT inhibitor – significantly improved cardiac diastolic function in HFpEF mice. These findings establish hepatic AGT as a causal contributor to HFpEF pathogenesis and reveal its therapeutic targeting as a promising strategy.
研究领域:
心脏病学
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分子生物学
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药理学
·
代谢疾病
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信号转导
✓ 已验证
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
BIOMATERIALS
·
2025
·
IF 12.9
Zixuan Dong,Song Liu,Xiaobing Liu,Dong He,Qi Chu,Linjie Zhong,Xiangyu Yu,Xiaoling Fu
Diabetes is closely associated with the onset and prognosis of myocardial infarction (MI). However, current treatment strategies primarily focus on addressing MI, often neglecting the detrimental effects of hyperglycemia, a hallmark of diabetes. Hyperglycemia disrupts the crucial transition of macrophages from the M1 to M2 phenotype, thereby exacerbating MI-induced tissue damage and impeding myocardial repair. Mitochondria have emerged as key regulators of macrophage phenotype, suggesting the potential for modulating macrophages through mitochondria transfer. In this study, we developed microvesicles containing active mitochondria (Mito@euMVs), derived from enucleated mesenchymal stem cells. We found that 86.3% of the Mito@euMVs contained mitochondria, with no nuclear material present. Mito@euMVs effectively delivered mitochondria into macrophages, facilitating their transit from M1 to M2 phenotype, even in hyperglycemia. Further in vivo study using a diabetic rat model of MI confirmed their cardiac repair properties. Treatment of Mito@euMVs led to 24.55±4.33% improvement in ejection fraction and 15.48±4.04% in fractional shortening 28 days post-MI in diabetic rats. Additionally, Mito@euMVs mitigated infarcted left ventricular wall thinning and fibrosis, enhanced M2 macrophage phenotype, promoted cardiomyocyte survival. Our study emphasizes the effective modulation of macrophage phenotype via mitochondrial transfer with Mito@euMVs and highlights their promising potential in treating MI.
研究领域:
心脏病学
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糖尿病研究
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再生医学
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细胞生物学
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免疫学
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干细胞治疗
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分子生物学
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生物医学研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）