JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 20
·e70144
·
IF 4.3
Qiying Yao,Xinrui Hu,Tiantian Bian,Qing Zhang,Zhao Xue,Yuesheng Lv,Shupeng Ren,Yue Chen,Dongmei Zhang,Liang Chen
Sialylation catalysed by sialyltransferase 7A (SIAT7A) plays a role in the development of cardiac hypertrophy. However, the regulatory mechanisms upstream of SIAT7A in this context remain poorly elucidated. Previous study demonstrated that KLF4 activates the SIAT7A gene in ischemic myocardium by binding to its promoter region. Nevertheless, the potential involvement of KLF4 in regulating SIAT7A expression in Ang II-induced hypertrophic cardiomyocytes remains uncertain. This study seeks to deepen the underlying mechanisms of the KLF4 and SIAT7A interaction in the progression of Ang II-induced cardiac hypertrophy. The results showed a concurrent increase in SIAT7A and KLF4 levels in hypertrophic myocardium of essential hypertension patients and in hypertrophic cardiomyocytes stimulated by Ang II. In vitro experiments revealed that reducing KLF4 levels led to a decrease in both SIAT7A synthesis and Sialyl-Tn antigen expression, consequently inhibiting Ang II-induced cardiomyocyte hypertrophy. Intriguingly, reducing SIAT7A levels also resulted in decreased KLF4 expression and suppression cardiomyocyte hypertrophy. Consistent with this, elevating SIAT7A levels increased KLF4 expression and exacerbated cardiomyocyte hypertrophy in both in vivo and in vitro experiments. Additionally, a time-course analysis indicated that KLF4 expression preceded that of SIAT7A. Luciferase reporter assays further confirmed that modulating SIAT7A levels directly influenced the transcriptional activity of KLF4 in cardiomyocytes. In summary, KLF4 expression is upregulated in cardiomyocytes treated with Ang II, which subsequently induces the expression of SIAT7A. The elevated levels of SIAT7A, in turn, enhance the transcription of KLF4 . These findings suggest a positive feedback loop between KLF4 and SIAT7A-Sialyl-Tn, ultimately promoting Ang II-induced cardiac hypertrophy.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
高影响因子
Biomed Research International
·
2022
·
IF 3.246
Shisheng Jiang,Chaoming Huang,Shulin Wang,Biyun Huang,Dan Wu,Guodong Zheng,Yi Cai
Objective. Through a network pharmacology method, we screened the main active compounds of Citri Reticulatae Pericarpium (CRP), constructed a drug-ingredient-disease-target network, explored the molecular mechanism of its treatment of myocardial hypertrophy, and validated it by using molecular biology approach. Methods. Traditional Chinese Medicine Systems Pharmacology (TCMSP) and GeneCards were utilised to collect the effective component in CRP and the targets of CRP and myocardial hypertrophy. The STRING database constructed the protein interaction network. The drug-ingredient-disease-target network was outlined by the Cytoscape 3.9.0 software. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the Metascape database. Real-time PCR (RT-PCR) and Western blotting were utilised to determine the mRNA and protein level of the critical targets of CRP therapy for myocardial hypertrophy. Results. We found that five practical components of CRP exerted therapeutic effects on myocardial hypertrophy by modulating 41 targets. Further analysis revealed that naringenin was the essential active compound in CRP that regulated myocardial hypertrophy. In addition, we showed that the active compounds of CRP might exert antihypertrophy effects via regulating essential target proteins such as AKT1-, MAPK3-, PPARA-, PPARG-, and ESR1-mediated signaling pathways such as cell proliferation, nuclear receptor activation, and oxidative stress. The molecular biology experiments demonstrated that naringenin inhibited the mRNA level of NPPA and NPPB induced by Ang II and regulated related targets such as AKT1, MAPK3, PPARA, PPARG, and ESR1. Conclusion. CRP could inhibit myocardial hypertrophy through multitarget and multiapproach.
研究领域:
药理学
·
分子生物学
·
中医药学
·
心脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Qian Liu,Cheng Xu,Jing Jin,Wenxiang Li,Jingjia Liang,Shijie Zhou,Zhenkun Weng,Yong Zhou,Xudong Liao,Aihua Gu
Lead (Pb) is widely used in industrial and daily-use consumer products. Early-life exposure may increase the risk of lead-related heart problems in childhood. However, the effects of early-life lead exposure on fetal heart development and long-term cardiac outcomes are unknown. In this study, pregnant ICR mice were exposed to lead acetate trihydrate (50 mg/kg/d) via oral gavage from gestation day 1.5 until offspring weaning. Thereafter, the second hit model was established, two groups of offspring (4 weeks old) were either administered sterile saline or Angiotensin II (Ang II) for 4 weeks until euthanasia. We investigated lead-induced offspring heart damage from embryonic period to adulthood by echocardiographic analysis, pathological H&E staining, and ultrastructural examination, as well as mitochondrial function detection. The results showed early-life lead exposure predisposed offspring mice to decreased ejection fraction, increased left ventricular volume, accompanied by hypertrophy and dilation, cardiomyocyte sarcomere dysplasia, abnormal mitochondrial structure, mitochondrial dysfunction, and decreased expression of key sarcomeric and mitochondrial genes, rendering them more susceptible to cardiac hypertrophy, vascular wall thickening, cardiac fibrosis, apoptosis, and heart failure induced by Ang II infusion. This study elucidates early-life low dose lead exposure compromises cardiac development and exacerbates second hit-induced cardiac pathological responses in adulthood, which furnishes crucial scientific evidence pertaining to the cardiac toxicity and risk evaluation associated with early-life exposure to lead.
研究领域:
毒理学
·
心血管医学
·
发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 9
·365
·
IF 5.4
Meijie Xu,Zhen Fan,Dingfu Wang,Dan Li,Haimiao Zou,Yiting Xue,Shixin Wang,Chunxia Li
Cardiac hypertrophy is a critical contributor to cardiac dysfunction and the development of heart failure, yet effective therapeutic strategies remain limited. Propylene glycol alginate sulfate sodium (PSS) is a marine sulfated polysaccharide drug used in the treatment of cardiovascular diseases and has shown cardiac function benefits. Here, we designed a pH-responsive PSS-loaded nanoparticle drug delivery system. It was self-assembled by negatively charged PSS with positively charged trimethyl chitosan glycocholic acid (TMC-GA) via electrostatic interaction, and further stabilized the nanoparticles with Hydroxypropyl methylcellulose phthalate (HP55) excipients. The prepared TMC-GA/HP55@PSS nanoparticles were spherical, with a mean particle size of 361.5 ± 1.26 nm, zeta potential of −30.3 ± 0.9 mV, and encapsulation efficiency of 92.52 ± 2.4%. In vitro release study demonstrated the pH-responsive property of TMC-GA/HP55@PSS under intestinal conditions and facilitated nanoparticles absorption in the intestinal epithelium. In vitro experiments confirmed the biocompatibility of PSS and its ability to improve myocardial cell hypertrophy. In vivo, both PSS and its nanoparticles significantly ameliorated pressure overload–induced cardiac hypertrophy in mice, with TMC-GA/HP55@PSS exhibiting better cardioprotective efficacy. This study is the first to integrate pH-responsiveness and bile acid transport-mediated uptake into PSS nanocarrier systems. The findings provide valuable data and enlightenment for designing novel formulations and expanding the clinical applications of PSS.
研究领域:
心血管药理学
·
纳米医学
·
药物递送
·
分子心脏病学
·
生物材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2024
·
IF 4.2
Jianmin Gong,Bo Shi,Ping Yang,Adeel Khan,Tao Xiong,Zhiyang Li
Background Hypertrophic cardiomyopathy (HCM) is a dominantly inherited disease associated with sudden immune cell associations that remain unclear. The aim of this study was to comprehensively screen candidate markers associated with HCM and immune cells and explore potential pathogenic pathways.Methods First, download the GSE32453 dataset to identify differentially expressed genes (DEGs) and perform Gene Ontology and pathway enrichment analysis using DAVID and GSEA. Next, construct protein-protein interaction (PPI) networks using String and Cytoscape to identify hub genes. Afterward, use CIBERSORT to determine the proportion of immune cells attributed to key genes in HCM and conduct ROC analysis based on the external dataset GSE36961 to evaluate their diagnostic value. Finally, validate the expression of key genes in the hypertrophic cardiomyocyte model through qRT-PCR using data from the HPA database.Results Comprehensive analysis revealed that there were 254 upregulated genes and 181 downregulated genes in HCM. The enrichment study underscored pathways of inflammatory signaling, including MAPK and PI3K-Akt pathways. Pathways abundant in genes associated with HCM encompassed myocardial contraction and NADH dehydrogenase activity. Additionally, the analysis of immune infiltration revealed a notable increase in macrophages, NK cells, and monocytes in the HCM group, showing statistically significant variances in CD4 memory resting T cell infiltration when compared to the healthy control group. Within the validation dataset GSE36961, the Area Under the Curve (AUC) scores for eight crucial genes (FOS, CD86, CD68, BDNF, PIK3R1, PLEK, RAC2, CCL2) each exceeded 0.8. The HPA database revealed the positioning traits and paths of these eight crucial genes in smooth muscle cells, myocardial cells, and fibroblasts. The outcomes of the qRT-PCR were aligned with the sequencing findings.Conclusion Bioinformatics analysis unveiled pivotal genes, pathways, and immune involvement, illuminating the molecular underpinnings of HCM. These findings suggest promising therapeutic targets for clinical applications.
研究领域:
医学
·
遗传学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2018
·Vol. 18
·期 5
·4349-4355
·
IF 1.922
Hangyu Tian,Dan Yu,Yan Hu,Pan Zhang,Yang Yang,Qiang Hu,Ming Li
Angiotensin II (Ang II) is a principal molecule of the renin‑angiotensin system, which promotes hypertrophy and fibrosis. It has been demonstrated that Ang II upregulates the expression of cyclophilin A (CypA), which is a potential myocardial hypertrophy factor. However, the mechanisms by which Ang II induces the expression of CypA in cardiomyocytes remain unclear. In the present study, reactive oxygen species (ROS) were detected by fluorescence microscopy, and western blot analysis and ELISA were used to measure CypA expression. It was identified that Ang II enhanced the production of ROS in rat cardiomyocytes. ROS, in turn, promoted CypA expression and secretion. Notably, the action of Ang II was primarily dependent on the angiotensin type 2 receptor (AT2R), not the type 1 receptor. These results provided an insight into the role of the AT2R signaling pathway in Ang II‑induced myocardial hypertrophy.
研究领域:
心脏病学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
·
IF 2.466
Fan Chen,Dandan Chen,Yubin Zhang,Liang Jin,Han Zhang,Miyang Wan,Tianshu Pan,Xiaochuan Wang,Yuheng Su,Yitao Xu,Junmei Ye
Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro . Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.
研究领域:
心脏病学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2025
·Vol. 20
·期 1
·1-20
·
IF 5.7
Liu Changtong,Guo Rui,Zhou Yue,Zhu Miao,Shao Li,Wang Yingchao,Zhao Lu
Background Cardiac hypertrophy, characterized by the thickening of the heart muscle, arises from factors such as hypertension and genetic mutations, often leading to adverse outcomes like heart failure and arrhythmias. Guanxinning tablets (GXNT), a botanical drug composed of the blood-activating herbs Salvia miltiorrhiza Bunge. and Ligusticum striatum DC., are widely used in the treatment of cardiovascular diseases. However, the active ingredients and their molecular mechanisms are yet to be fully understood. Methods We evaluated the anti-hypertrophic effects of GXNT and screened its active substances via cardiac function live-imaging on an aristolochic acid A-stimulated zebrafish cardiac hypertrophy model, and through F-actin immunostaining on a phenylephrine-induced hypertrophic NRCMs model. Additionally, the protective effects of GXNT’s active substances were analyzed in a mouse model of cardiac hypertrophy using echocardiography, histopathology analysis, and western blotting. Results The anti-hypertrophic effects of GXNT were assessed using an aristolochic acid A-stimulated zebrafish model and phenylephrine-induced hypertrophic NRCMs. GXNT demonstrated significant anti-hypertrophic effects in both models. Phenotypic screening identified Senkyunolide I (Sen I) from Ligusticum striatum as the active component in the zebrafish model, while Salvianolic acid B (Sal B) and Rosmarinic acid from Salvia miltiorrhiza emerged as the key anti-hypertrophic compound in NRCMs. In a mouse model of isoproterenol-induced cardiac hypertrophy, Sal B and Sen I showed synergistic effects, improving cardiac function, reducing oxidative stress, and suppressing inflammation. Mechanistically, transcriptomic sequencing highlighted cooperative modulation of MAP3K1 signaling by the two compounds. Notably, siRNA-mediated knockdown of MAP3K1 in cardiomyocytes attenuated the hypertrophic phenotype, supporting its essential role in the pathological process. Molecular docking and dynamic simulations further supported their binding potential to MAP3K1. Conclusion These findings underscore GXNT’s potent anti-hypertrophic effects, possibly driven by the synergistic actions of Sal B and Sen I, and offer insights into its therapeutic potential through MAP3K1 signaling regulation.
研究领域:
心血管药理学
·
分子药理学
·
中药学
·
信号转导
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY INTERNATIONAL
·
2018
·Vol. 42
·期 11
·1584-1593
·
IF 1.936
Bo Yu,Yanan Zhao,Hongli Zhang,Di Xie,Wei Nie,Kaiyao Shi
MicroRNA-143-3p (miR-143-3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR-143-3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H 2 O 2 administration in vitro. The expression status of miR-143-3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR-143-3p inhibition on H 2 O 2 -induced changes in ERK5/PPARδ/NF-κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR-143-3p and p-ERK5. However, the up-regulated expression of miR-143-3p had no effect on the expression of ERK5, which was a direct target of miR-143-3p. The results of in vitro assays showed that H 2 O 2 administration increased the levels of miR-143-3p and p-EKR5 and induced the activation of NF-κB pathway. After the inhibition of miR-143-3p, the activation of EKR5 and NF-κB pathway was suppressed, whereas the expression of PPARδ was up-regulated. The current study demonstrated that miR-143-3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR-143-3p up-regulation appears to be a complementary response to induce the subsequent anti-inflammatory signaling transduction, which needed further exploration.
研究领域:
心血管疾病
·
分子生物学
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Yuhang Gong,Da Wo,Canran Wang,Ruokun Huang,En Ma,Celiang Wu,Jun Peng,Weidong Zhu,Dan-ni Ren
Background: Angiotensin II (Ang II) type 1 receptor (AT1R) signaling pathway is a key component of the renin-angiotensin-aldosterone system (RAAS) that is involved in the development of hypertension. Chronic Ang II overactivation results in pathological cardiac hypertrophy that progresses into decompensated cardiac dysfunction and impairment. Qingda granule (QDG) is a Traditional Chinese formula that has been used clinically in treating hypertension and its complications.Purpose: This study aimed to elucidate the role and underlying mechanisms of QDG in preventing Ang II-induced cardiac hypertrophy.Methods: We used chronic Ang II infusion via minipumps in mice and administered QDG daily to examine the effects of QDG on preventing hypertension and various parameters of cardiac impairment.Results: QDG treatment significantly reduced Ang II-induced elevation in blood pressure. Furthermore, QDG exerted a robust cardioprotective effect on chronic Ang II-induced cardiac hypertrophy and decompensated cardiac dysfunction. QDG also inhibited Ang II-induced adverse NF-κB signaling activation and downstream pro-inflammatory targets, which were prevented via administration with SC75741, a specific NF-κB inhibitor.Conclusion: Our findings provide further insight into the robust ability of QDG in preventing Ang II-induced cardiac hypertrophy via preventing NF-κB signaling activation and implicate its use in the clinical treatment of hypertension and cardiac hypertrophy.
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2025
·
IF 3.4
Pingge Tian,Lei Xu,Fan Zou,Qian Jia,Yangjian Liu,Jin Chen,Pengzhen Wang
Background: Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease characterized by left ventricular hypertrophy and excessive myocardial contraction. Endothelial cells (ECs) play a key role in the pathogenesis of HCM, and their secreted growth factors regulate the growth and function of cardiomyocytes. However, the specific molecular mechanisms and biomarkers associated with endothelial dysfunction in HCM remain unclear. Methods: Single-cell RNA sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) database (GSE255296), and bulk RNA sequencing data were obtained from GSE249925 and GSE180313. The scRNA-seq data were processed using the Seurat package for cell type annotation and batch effect removal. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed, and pathway activity was evaluated using the AUCell algorithm. SCENIC was applied to construct transcription factor-specific regulatory networks. Differential gene expression analysis was conducted using the limma package, and key genes were determined by intersecting differentially expressed genes (DEGs) with EC-specific highly expressed genes. The diagnostic efficacy of these key genes was assessed via receiver operating characteristic (ROC) curve analysis. The mRNA expression of genes in HUVECs treated with or without angiotensin II (Ang II) was assessed using qPCR. Cell viability was determined using the CCK-8 assay, and cell invasive ability was evaluated through Transwell assays to investigate the regulatory effect of TMTC1 overexpression on Ang II-induced injury in HUVECs. Results: Seven major cell types were identified, with cardiomyocytes and ECs being the main cell populations in HCM. KEGG enrichment analysis revealed significant activation of pathways such as the transforming growth factor-beta (TGF-β) signaling pathway in ECs. High-activity transcription factors NFIB, MECOM, and FLI1 were identified in ECs, whose target genes were enriched in processes related to cell morphogenesis. Three key genes-TMTC1, RPS6KA2, and F8-were selected based on differential expression and EC specificity. These genes were lowly expressed in HCM and exhibited high diagnostic efficacy, with area under the curve (AUC) values > 0.7. Ultimately, the CCK-8 assay results indicated that Ang II inhibited the viability of HUVECs, and this inhibitory effect could be reversed by the overexpression of TMTC1 (oe-TMTC1). Furthermore, Transwell assays indicated that Ang II impaired cellular migration, and this impairment could be restored by oe-TMTC1. Conclusion: The identified key genes and pathways provide new targets for therapeutic intervention and contribute to a deeper understanding of the pathogenesis of HCM.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Cardiovascular Disorders
·
2024
·Vol. 24
·期 1
·1-12
·
IF 2
Qian Kai,Song Li,Guo Jia-Min,Fu Dan,Shi Jia,Ma Yu,Ge Zi-Jie,Li Lei,Zhang Su-qin
Background Cardiovascular disease carries the highest mortality rate among diseases, and pharmacological interventions have limited efficacy. Baicalin (Bai) promotes biological metabolic processes, eliminates oxygen free radicals, and is anti-inflammatory. This study aimed to investigate the effect of Bai on the cardiac injury model induced by isoproterenol in mice.Methods and ResultIn this study, all groups except the control received intraperitoneal injections of isoproterenol (ISO) to induce a cardiac injury model, with the drug administered continuously for 14 days. hematoxylin and eosin staining and Masson’s trichrome staining revealed that Bai significantly mitigated ISO-induced pathological changes in mouse heart tissue and alleviated myocardial hypertrophy. Echocardiography assessments demonstrated that Bai preserved cardiac function in ISO-treated mice. Furthermore, our findings indicated that Bai activated the Nrf2 signaling pathway in vivo and in vitro. To delve deeper, mice were further treated with ML385 (ML) via intraperitoneal injection to inhibit the Nrf2 pathway. Results showed that ML385 blocked the cardioprotective effects of Bai in mouse heart tissue.Conclusion Bai protects against ISO-induced cardiac injury, and its mechanism is related to activating the Nrf2/HO-1 signaling pathway to regulate cardiac ferroptosis and improve cardiac remodeling.
研究领域:
心血管疾病
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）