Cardiovascular Diagnosis and Therapy
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2024
·Vol. 14
·期 4
·576
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IF 2.1
Meili Zhu,Jiangbiao Hu,Yifan Pan,Qian Jiang,Chang Shu
Background Heart failure (HF) remains one of the most common events in the progression of hypertension. Magnoflorine (MNF) has been shown beneficial effects on the cardiovascular system. However, the action of MNF on angiotensin (Ang) II-induced cardiac remodeling and its underlying mechanisms have not yet been characterised. Here, we assessed the action of MNF in the development of hypertension-related HF. Methods C57BL/6 male mice were subjected to Ang II through a micro-osmotic pump infusion continuously for 4 weeks to induce hypertensive HF. MNF (10 and 20 mg/kg) was administered in the final 2 weeks. Ang II content was measured by enzyme-linked immunosorbent assay (ELISA) kit. Values of ejection fraction (EF) and fractional shortening (FS) were detected using an ultrasound diagnostic instrument. The mRNA levels of hypertrophic and fibrotic genes were determined by real-time quantitative polymerase chain reaction (RT-qPCR). Haematoxylin and eosin (H&E), wheat germ agglutinin (WGA), Masson trichrome, and Sirius Red staining were used to analyse pathologic changes in heart tissues. The expression levels of phosphorylated AMP-activated protein kinase (AMPK), light chain 3 microtubule associated protein II (LC3 II) to LC3 I, and p62 were detected by western blot assay. Results MNF significantly improved cardiac dysfunction and the content of creatine kinase-MB without altering blood pressure in Ang II-challenged mice. MNF obviously corrected the phenotypes of cardiac hypertrophy and fibrosis, including the high mRNA levels of atrial natriuretic peptide ( Anp ), brain natriuretic peptide ( Bnp ), collagen1a ( Col1a1 ), transforming growth factor beta ( Tgfb1 ), enlarged myocardial areas, and increased positive areas of Masson trichrome and Sirius Red staining. In addition, MNF alleviated oxidative injury, reflected by the upregulation of glutathione and the downregulation of reactive oxygen species and malondialdehyde. The activation of AMPK was elevated accompanied by an increased level of autophagy by MNF in hypertensive heart tissues. The therapeutic action of MNF was confirmed in Ang II-challenged H9c2 cells. Specifically, the AMPK inhibitor could eliminate the autophagy pathway in which MNF is involved. Conclusions MNF has benefits in hypertension-induced cardiac remodeling, which was partially associated with the improvement of oxidative stress via the mediation of the AMPK/autophagy axis.
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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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Shijie Fan,Ying Zhao,Qingqing Zhao,Diyun Xu,Xi Chen,Jibo Han,Ziming Fang,Guang Liang,Yunjie Zhao
Hypertension engenders numerous complications, including hypertensive renal disease (HRD). Recent studies have underscored the significance of redox homeostasis in hypertension-associated kidney disorders. Carnosol (Car) has been identified as a potent antioxidant in other diseases. Nevertheless, its role in HRD remains uncertain. This research evaluated the therapeutic impact of Car on HRD and explored its pharmacological mechanism. Car (40 mg/kg) effectively ameliorated kidney injury and oxidative stress (OS) induced by angiotensin II (Ang II) both in vitro and in vivo. Mechanistically, Car facilitates the phosphorylation of p62 through its interaction with mTOR, leading to the degradation of KEAP1, the release of NRF2, and the subsequent upregulation of antioxidant genes. Blocking mTORC1 eliminated Car-induced p62 activation and its antioxidant functions. In summary, our research has demonstrated that Car activates the p62-KEAP1-NRF2 pathway to alleviate the kidney injury and OS caused by Ang II. Consequently, Car may emerge as a promising candidate for the prevention and treatment of Ang II-induced kidney injury.
研究领域:
药理学
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分子生物学
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肾脏病学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 20
·e70144
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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
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分子生物学
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细胞生物学
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DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2020
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IF 4.545
Jingsi Zhang,Xiaodan Fu,Li Yang,Hongxin Wen,Lijiao Zhang,Fengyi Liu,Yu Lou,Qian Yang,Yanchun Ding
Cardiac hypertrophy and remodeling are among the major health challenges facing countries around the world today. Neohesperidin plays an important role in influencing cell apoptosis, cell growth, tumorigenesis and tumor microenvironment, but the mechanism and role of Neohesperidin in cardiac hypertrophy and remodeling caused by Angiotensin II has not been fully elucidated. This study used Angiotensin II to induce cardiac hypertrophy and cardiac remodeling in mice. Echocardiography was used to evaluate cardiac function, H&E and Masson trichrome staining were used to detect myocardial histological changes. Cardiac cell size was determined by WGA staining. The protein content of the signaling pathway was detected by Western blot, and the mRNA expression of fibrosis and hypertrophy markers was detected by qPCR. DHE staining was used to detect oxidative stress. We also observed the effect of Neohesperidin on Ang II-induced NRCMs. The results showed that neohesperidin can significantly inhibit Ang II-induced myocardial contractile dysfunction, cardiac hypertrophy, myocardial fibrosis, myocardial oxidative stress and inflammation. These results suggest that Neohesperidin can alleviate cardiac hypertrophy and remodeling caused by Ang II, and its mechanism may be related to the inhibition of multiple signaling pathways.
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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DOI
PubMed
高影响因子
HYPERTENSION RESEARCH
·
2019
·Vol. 43
·期 3
·168-177
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IF 3.217
Bi Hai-Lian,Zhang Yun-Long,Yang Jie,Shu Qing,Yang Xiao-Lei,Yan Xiao,Chen Chen,Li Zhi,Li Hui-Hua
Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.
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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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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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.
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DOI
PubMed
高影响因子
Journal of Ginseng Research
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2025
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IF 5.6
Risheng Zhao,Zhuoqun Wang,Chang Liu,Linxin Zhang,Min Zhang,Huizhu Du,Gege Yang,Haiming Sun,Wei Liu,Shuang Yan,Mengyang Wang
Background (20S)-Protopanaxatriol (PPT), a bioactive triterpenoid from Panax ginseng , has been used in Traditional Chinese Medicine (TCM) to tonify kidney yang and regulate blood pressure. The research aimed to elucidate PPT's protective effects against angiotensin II (Ang II)-induced renal injury. Methods A C57BL/6 mouse model of kidney injury was established by continuous infusion of Ang II for 4 weeks using an osmotic minipump. Treatment with PPT was initiated two weeks after Ang II infusion and administered daily for 14 days. Molecular docking, drug affinity response target stability (DARTS), and cellular thermal shift assay (CETSA) were employed to identify and validate potential targets of PPT in alleviating Ang II-induced renal injury. Additionally, biochemical assays, histopathological analysis, and Western blotting were performed to assess renal function, tissue damage, and signaling pathway modulation. Results Our findings demonstrated that PPT exerted protective effects against Ang II-induced renal dysfunction in mice by significantly attenuating renal fibrosis and inflammation. Mechanistically, PPT targeted PTPN1 and inhibited the AMPK/mTOR signaling pathway, thereby effectively alleviating autophagy dysregulation in both renal tissues of mice and Ang II-stimulated NRK-52E cells in vitro. Molecular docking, DARTS, and CETSA experiments confirmed PTPN1 as a direct target of PPT, providing a molecular basis for its renoprotective effects. Conclusion These findings validate ginseng's traditional use in kidney disorders and demonstrate PPT's potential as a therapeutic agent for hypertensive nephropathy by targeting PTPN1/AMPK/mTOR signaling. Further clinical exploration is needed to translate these results into practice.
研究领域:
药理学
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肾脏病学
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中医中药
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分子生物学
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信号转导
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cardiovascular Medicine
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2022
·
IF 5.846
Kai-Wen Ren,Xiao-Hong Yu,Yu-Hui Gu,Xin Xie,Yu Wang,Shi-hao Wang,Hui-Hua Li,Hai-Lian Bi
Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.
研究领域:
心脏病学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Gu Yu-Hui,Ren Kai-Wen,Wang Yu,Wang Shi-Hao,Yu Xiao-Hong,Xu Li-Wen,Li Hui-Hua,Bi Hai-Lian
Hypertension is one of the common causes of pathological cardiac hypertrophy and a major risk for morbidity and mortality of cardiovascular diseases worldwide. Ubiquitin-Specific Protease 7 (USP7), the first identified deubiquitinating enzymes, participated in a variety of biological processes, such as cell proliferation, DNA damage response, tumourigenesis, and apoptosis. However, its role and mechanism in cardiac remodeling remain unclear. Here, our data indicated that USP7 expression was increased during Ang II-induced cardiac hypertrophy and remodeling in mice and humans with heart failure, while the administration of its inhibitor p22077 attenuated cardiac hypertrophy, cardiac fibrosis, inflammation, and oxidase stress. Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-β/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF.
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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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
·
IF 6.656
Mengyang Wang,Wu Luo,Tianxiang Yu,Shiqi Liang,Chunpeng Zou,Jinfeng Sun,Gao Li,Guang Liang
Background Heart failure is a common event in the course of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertension-related cardiac inflammation and remodeling. A naturally occurring compound, diacerein , exhibits anti-inflammatory activities in various systems. Hypothesis/Purpose In this study, we have examined the potential effects of diacerein on Ang II-induced heart failure. Methods C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop hypertensive heart failure. Mice were treated with diacerein by gavage for final 2 weeks. RNA-sequencing analysis was performed to explore the potential mechanism of diacerein. Results We found that diacerein could inhibit inflammation, myocardial fibrosis , and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. To explore the potential mechanism of diacerein, RNA-sequencing analysis was performed, indicating that MAPKs/c-Myc pathway is involved in that cardioprotective effects of Diacerein. We further confirmed that diacerein inhibits Ang II-activated MAPKs/c-Myc pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes . Deficiency of MAPKs or c-Myc in cardiomyocytes abolished the anti-inflammatory effects of diacerein. Conclusion Our results indicate that diacerein protects hearts in Ang II-induced mice through inhibiting MAPKs/c-Myc-mediated inflammatory responses, rendering diacerein a potential therapeutic candidate agent for hypertensive heart failure.
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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炎症
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
·
IF 7.419
Mengyang Wang,Wu Luo,Tianxiang Yu,Shiqi Liang,Jinfeng Sun,Yi Zhang,Xue Han,Xiaohong Long,Guang Liang,Gao Li
Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB 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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炎症研究
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产品关联
DOI
PubMed
高影响因子
Translational Research
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2021
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IF 7.012
Shiju Ye,Ke Lin,Gaojun Wu,Ming-Jiang Xu,Peiren Shan,Weijian Huang,Yi Wang,Guang Liang
Activation of the innate immune system represents a vital step in inflammation during cardiac remodeling induced by the angiotensin II (Ang II). This study aimed to explore the role of Toll-like receptors 2 (TLR2) in Ang II-induced cardiac remodeling. We investigated the effect of TLR2 deficiency on Ang II-induced cardiac remodeling by utilizing TLR2 knockout mice, bone marrow transplantation models, and H9C2 cells. Though TLR2 deficiency had no effect on body weight change , cardiac Ang II content and blood pressure, it significantly ameliorated cardiac hypertrophy, fibrosis and inflammation, as well as improved heart function. Further bone marrow transplantation studies showed that TLR2-deficiency in cardiac cells but not bone marrow-derived cells prevented Ang II-induced cardiac remodeling and cardiac dysfunction. The underlying mechanism may involve increased TLR2-MyD88 interaction. Further in vitro studies in Ang II-treated H9C2 cells showed that TLR2 knockdown by siRNA significantly decreased Ang II-induced cell hypertrophy, fibrosis and inflammation. Moreover, Ang II significantly increased TLR2-MyD88 interaction in H9C2 cells in a TLR4-independent manner. TLR2 deficiency in cardiac cells prevents Ang II-induced cardiac remodeling, inflammation and dysfunction through reducing the formation of TLR2-MyD88 complexes. Inhibition of TLR2 pathway may be a therapeutic strategy of hypertensive heart failure.
研究领域:
心脏病学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
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