Nature Communications
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2024
·Vol. 15
·期 1
·1-20
·
IF 14.7
Chen Jinyong,Ren Tanchen,Xie Lan,Hu Haochang,Li Xu,Maitusong Miribani,Zhou Xuhao,Hu Wangxing,Xu Dilin,Qian Yi,Cheng Si,Yu Kaixiang,Wang Jian`an,Liu Xianbao
Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790—an anti-calcification drug—to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient ( Ldlr −/− ) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.
研究领域:
心血管疾病
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药物递送
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Cardiovascular Research
·
2025
·
IF 10.8
Zhang Jingjing,Tang Yuyi,Zhang Shan,Xie Zhuxin,Ma Wenrui,Liu Shaowen,Fang Yixuan,Zheng Shufen,Huang Ce,Yan Guoquan,Abudupataer Mieradilijiang,Xin Yue,Zhu Jingqiao,Han Wenjing,Wang Weizhong,Shen Fenglin,Lai Hao,Liu Yang,Ye Dan,Yu Fa-Xing,Xu Yanhui,Pan Cuiping,Wang Chunsheng,Zhu Kai,Zhang Weijia
Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD + salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD + transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt , Nmnat1 , Nmnat3 , Slc25a51 , Nadk2 and Aldh18a1 , genes involved in NAD + salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.
研究领域:
心血管疾病
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分子生物学
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遗传学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
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2015
·Vol. 12
·期 5
·6656-6662
·
IF 1.554
Chengfei Zheng,Hui Niu,Ming Li,Hongkun Zhang,Zhenggang Yang,Lu Tian,Ziheng Wu,Donglin Li,Xudong Chen
Aortic aneurysm is a cardiovascular condition with a serious risk of mortality and the dismal prognosis of any type of major cardiovascular disease. The present study found that tissues from aortic aneurysm patients and hypoxic aortic smooth muscle cells showed aberrant high expression of the cyclic RNA hsa‑circ‑000595, as demonstrated by polymerase chain reaction array screening. Knockdown of hsa‑circ‑000595 resulted in a decreased apoptotic rate of human aortic smooth muscle cells. Furthermore, it was determined that miR‑19a is a target of hsa‑circ‑000595. The results of the present study laid an epigenetic foundation for exploring the underlying mechanisms of the development of aortic aneurysm.
研究领域:
心血管疾病
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分子生物学
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表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yu Shi,Yi Zhao,Si-Jia Sun,Xiu-Ting Lan,Wen-Bin Wu,Zhen Zhang,Yu-Xin Chen,Yu-Ying Yan,Yu-Ping Xu,Dong-Jie Li,Hui Fu,Fu-Ming Shen
Abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of glutathione peroxidase 4 (GPX4) itself determined ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.
研究领域:
心血管疾病
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2023
·
IF 6.1
Xie Wenqing,Shan Yue,Wu Zhuonan,Liu Nan,Yang Jinjin,Zhang Hanlin,Sun Shiming,Chi Jufang,Feng Weizhong,Lin Hui,Guo Hangyuan
Objectives To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Methods In vivo, we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR−/−/Herpud1−/−) mice and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression. Results Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-fed low-density lipoprotein receptor−/− (LDLR−/−) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions These findings identify a previously unknown mechanism of Herpud1 upregulation in Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. Highlights • Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD. • In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy. • 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice. Graphical Abstract
研究领域:
心血管疾病
·
分子生物学
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细胞生物学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2025
·
IF 4.1
Haipeng He,Lei Chen,Jiaxin Peng,Jinyan Guo,Xue Xiao,Chaoxun Dou,Huining Chen,Songbiao Zhan,Xue Han,Weifeng Yao
Oxidative stress, particularly ROS accumulation, plays a key role in the development of abdominal aortic aneurysm (AAA). Surgical treatments and current drugs for AAA have limitations, including lack of specificity and significant side effects. This study constructed ROS-responsive nanoparticles using phenylthio-modified dendritic polylysine (PDP) loaded with selenomethionine (PDPs-Se) for AAA treatment, and elucidated its mechanism of action. In-vitro studies revealed that PDPs-Se enhanced the clearance of ROS by increasing the levels of superoxide dismutase (SOD) and glutathione (GSH) while reducing malondialdehyde (MDA) levels. Furthermore, PDPs-Se upregulated the expression levels of GPX4, SLC7A11, and FTH1 to suppress ferroptosis and modulate the differentiation of vascular smooth muscle cells (VSMCs) from a synthetic to a contractile phenotype. In-vivo experiments revealed that PDPs-Se attenuated the progression of AAA by inhibiting oxidative stress responses and improving the aortic wall thickness, indicating its potential as an approach for AAA therapy.
研究领域:
医学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Longwu Xu,Lin Ma,Xiufeng Xu,Yifan Wang,Qiuhong Jiao,Shulan Pang,Yuying Wang,Weiwei Yang,Shuai Mao,Yudan Zhao,Jie Hao,Tao Huang,Peikang Dong,Yingshuai Wang,Tao Wang
Aortic dissection (AD) is a life-threatening condition with a high mortality rate. Oxidative stress and endothelial and vascular smooth muscle cell migration contribute to AD pathogenesis. Herein, we investigated the therapeutic potential of hydrogen (H2), delivered via magnesium diboride nanosheets (MBNs), in a murine model of β-aminopropionitrile-induced AD. This treatment significantly improved survival rate and reduced AD progression, as evidenced by improved aortic wall structure and reduced false lumen formation. Transcriptomic analysis indicated modulation of the RhoA/ROCK pathway, confirmed using Western blotting, immunohistochemistry, and immunofluorescence, which showed significant downregulation of RhoA and ROCK2 after 28 days of treatment (P < 0.05). These findings suggest that hydrogen released from MBNs attenuates AD progression through reactive oxygen species scavenging and RhoA/ROCK pathway inhibition.
研究领域:
医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Mengxiao Shi,Rui Liu,Hong Fang,Ying Wu,Cheng Chen,Bin Kong,Qing Zhou
Aortic dissection is a serious health risk and has led to interest in creating effective drug treatments like ketorolac. However, conventional administration techniques lack specificity, which limits their effectiveness and may result in adverse effects. A microneedle patch system (MNPS) offers a minimally invasive, pain-free alternative with a high capacity for drug delivery, but there is still a gap in the direction of treating aortic dissection. Here, we present a novel biodegradable MNPS with a pagoda-shaped structure designed for drug loading. These MNPS were fabricated using a stepwise mold replication method, with the medication embedded in the top layer of the MNPS. The double-layered pagoda structure enhances MNPS adhesion, enabling it to withstand the impact of aortic blood flow and enhancing drug targeting. In conclusion, our pagoda MNPS introduces a new approach for treating aortic dissection, providing hope for affected patients.
研究领域:
药剂学
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心血管医学
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生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Du Chen,Tiantian Song,Yi Liu,Ying Wang,Boyang Qin,Qingyi Zhang,Weipeng Hu,Xiqiao Zhou,Rong Qi
Endovascular aneurysm repair (EVAR) plays a crucial role in the treatment of abdominal aortic aneurysm (AAA) in the clinic, but the aneurysm remains in the patient's body after surgery, continuing to pose a risk of progression. Cycloastragenol (CAG) is proven to be an effective anti-AAA drug, and its vascular protective effects can be further improved when the hydrophobic CAG is encapsulated into nano-sized formulations to enhance its bioavailability. In this context, this study developed an extravascular patch hydrogel loaded with CAG nanostructured lipid carriers and a hydrophilic drug of doxycycline hydrochloride (DOX). The extravascular patch delivered onto the mouse abdominal aortas can promote local permeation of hydrophilic/hydrophobic drugs at the vessel sites and provide effective vascular protection against AAA injury induced by elastase. This study introduces a novel and promising approach for AAA treatment, which can serve as a supplementary strategy after EVAR surgery.
研究领域:
生物医学工程
·
药剂学
·
血管外科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LANGMUIR
·
2023
·
IF 3.9
Yuting Zhu,Kai Li,Qiang Zhang,Yifeng Nie,Tun Yan,Xiaoli Shi,Dong Han
Injectable hydrogels with strong mechanical properties have significant potential for biomedical applications, including the development of electronic skin, intelligent medical robots, as well as tissue engineering. In this study, we report on an injectable hydrogel with notable tensile strength and adhesion properties, achieved through cross-linking thiol-terminated four-arm poly (ethylene glycol) using silver-doped nano-hydroxyapatite, modified with dopamine. Subsequently, the hydrogel was injected in vivo through the perivascular interstitial space of rats. The hydrogel wrapped around the damaged abdominal aortic adventitia, which greatly increases the stress strength of the arterial adventitia. We found that the hydrogel was characterized by excellent biocompatibility, and it induced little immune response over a span of 21 days post-implantation. This simple and minimally invasive vascular protection strategy appears promising for the treatment of vascular diseases, such as abdominal aortic aneurysm (AAA).
研究领域:
生物医学工程
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组织工程
·
血管外科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2020
·
IF 2.598
Kaijie Wang,Jinping Zhao,Wenwen Zhang,Minglin Zhu,Ming Xu,Dan Li,Hongjie Shi,Ming Zhang,Jiajun Shi,Zhe Dong
Aortic dissection (AD) is a serious condition and a health issue on a global scale. β-Aminopropionitrile–induced AD in mice is similar to the pathogenesis of AD in humans. Resveratrol (RSV) is a natural polyphenolic substance that provides anti-inflammatory and cardiovascular effects, but the role of RSV in AD is unclear. In this study, we investigated the effects and mechanisms of RSV on β-aminopropionitrile–induced AD in mice. Our results indicate that RSV can prevent the occurrence of AD. More meaningfully, we found that the protective effect comprises an increase in sirtuin 1 (SIRT1) expression in endothelial cells for the reconstruction of their structure, reducing the recruitment of inflammatory cells by endothelial cells and inhibiting the inflammation response, thereby suppressing the occurrence of AD.
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
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
·
2024
·
IF 4.9
Xinjian Wang,Shuxian Han,Jinxiu Liang,Chen Xu,Ranran Cao,Shuoyang Liu,Yi Luan,Ying Gu,Peidong Han
Background Exosomes released by cardiomyocytes are essential mediators of intercellular communications within the heart, and various exosomal proteins and miRNAs are associated with cardiovascular diseases. However, whether the endosomal sorting complex required for transport (ESCRT) and its key component Alix is required for exosome biogenesis within cardiomyocyte remains poorly understood. Methods Super-resolution imaging was performed to investigate the subcellular location of Alix and multivesicular body (MVB) in primary cardiomyocytes. Cardiomyocyte-specific Alix-knockout mice were generated using AAV9/CRISPR/Cas9-mediated in vivo gene editing. A stable Alix-knockdown H9c2 cardiomyocyte line was constructed through lentiviral-mediated delivery of short hairpin RNA. In order to determine the role of Alix in controlling exosome biogenesis, exosomes from cardiomyocyte-specific Alix-knockout mice plasma and Alix-knockdown H9c2 culture medium were isolated and examined by western blot, NTA analysis and transmission electron microscopy. Biochemical and immunofluorescence analysis were performed to determine the role of ESCRT machinery in regulating MVB formation. Lastly, transverse aortic constriction (TAC)-induced cardiac pressure overload model was established to further explore the role of Alix-mediated exosome biogenesis under stress conditions. Results A significant proportion of Alix localized to the MVB membrane within cardiomyocytes. Genetic deletion of Alix in murine heart resulted in a reduction of plasma exosome content without affecting cardiac structure or contractile function. Consistently, the downregulation of Alix in H9c2 cardiomyocyte line also suppressed the biogenesis of exosomes. We found the defective ESCRT machinery and suppressed MVB formation upon Alix depletion caused compromised exosome biogenesis. Remarkably, TAC-induced cardiac pressure overload led to increased Alix, MVB levels, and elevated plasma exosome content, which could be totally abolished by Alix deletion. Conclusion These results establish Alix as an essential and stress-sensitive regulator of cardiac exosome biogenesis and the findings may yield valuable therapeutic implications.
研究领域:
心血管生物学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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