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Irqsusi M, Rodepeter FR, Günther M, Kirschbaum A, Vogt S. Matrix metalloproteinases and their tissue inhibitors as indicators of aortic aneurysm and dissection development in extracellular matrix remodeling. World J Exp Med 2025; 15:100166. [DOI: 10.5493/wjem.v15.i2.100166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 01/04/2025] [Accepted: 01/15/2025] [Indexed: 04/16/2025] Open
Abstract
Aneurysms and dissections represent some of the most serious cardiovascular diseases. The prevailing theory posits that mechanical overloading of the vessel wall is the underlying cause. Inspired by Barkhordarian et al, the authors present matrix metalloproteinases (MMPs) and their inhibitors in immunohistological analyses as contributing factors in the pathophysiology of aortic aneurysms (AA). Data analysis of MMP-1, MMP-9, tissue inhibitors of metalloproteinases (TIMPs), including TIMP-1 and TIMP-2 expression reveals a varied distribution between the adventitia and media and a non-uniform expression of the investigated markers. These elements, as key components of the extracellular matrix (ECM), indicate that the formation of AA is not solely driven by endoluminal pressure loading of the aortic wall. Instead, degenerative processes within ECM elements contribute significantly. Importantly, AA do not necessarily imply dissection. Tissue destruction, allowing blood flow entry, arises from reduced oxygen supply to the media, primarily due to incomplete capillarization or neocapillarization.
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Affiliation(s)
- Marc Irqsusi
- Department of Heart Surgery, Universitätsklinikum Marburg and Gießen GmbH, Marburg 35043, Hesse, Germany
| | - Fiona R Rodepeter
- Institute of Pathology, Philipps-University Marburg, Marburg 35043, Hesse, Germany
| | - Madeline Günther
- Department of Heart Surgery, Cardiovascular Research Laboratory, Philipps-University Marburg, Marburg 35043, Hesse, Germany
| | - Andreas Kirschbaum
- Department of Visceral Surgery, University Hospital Giessen and Marburg GmbH, Marburg 35043, Hesse, Germany
| | - Sebastian Vogt
- Department of Heart Surgery, Philipps-University Marburg, Marburg 35043, Hesse, Germany
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Zhang L, Zhou J, Kong W. Extracellular matrix in vascular homeostasis and disease. Nat Rev Cardiol 2025; 22:333-353. [PMID: 39743560 DOI: 10.1038/s41569-024-01103-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 01/04/2025]
Abstract
The extracellular matrix is an essential component and constitutes a dynamic microenvironment of the vessel wall with an indispensable role in vascular homeostasis and disease. From early development through to ageing, the vascular extracellular matrix undergoes various biochemical and biomechanical alterations in response to diverse environmental cues and exerts precise regulatory control over vessel remodelling. Advances in novel technologies that enable the comprehensive evaluation of extracellular matrix components and cell-matrix interactions have led to the emergence of therapeutic strategies that specifically target this fine-tuned network. In this Review, we explore various aspects of extracellular matrix biology in vascular development, disorders and ageing, emphasizing the effect of the extracellular matrix on disease initiation and progression. Additionally, we provide an overview of the potential therapeutic implications of targeting the extracellular matrix microenvironment in vascular diseases.
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Affiliation(s)
- Lu Zhang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
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Wu H, Li Z, Yang L, He L, Liu H, Yang S, Xu Q, Li Y, Li W, Li Y, Gong Z, Shen Y, Yang X, Huang J, Yu F, Li L, Zhu J, Sun L, Fu Y, Kong W. ANK Deficiency-Mediated Cytosolic Citrate Accumulation Promotes Aortic Aneurysm. Circ Res 2024; 135:1175-1192. [PMID: 39513269 DOI: 10.1161/circresaha.124.325152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND Disturbed metabolism and transport of citrate play significant roles in various pathologies. However, vascular citrate regulation and its potential role in aortic aneurysm (AA) development remain poorly understood. METHODS Untargeted metabolomics by mass spectrometry was applied to identify upregulated metabolites of the tricarboxylic acid cycle in AA tissues of mice. To investigate the role of citrate and its transporter ANK (progressive ankylosis protein) in AA development, vascular smooth muscle cell (VSMC)-specific Ank-knockout mice were used in both Ang II (angiotensin II)- and CaPO4-induced AA models. RESULTS Citrate was abnormally increased in both human and murine aneurysmal tissues, which was associated with downregulation of ANK, a citrate membrane transporter, in VSMCs. The knockout of Ank in VSMCs promoted AA formation in both Ang II- and CaPO4-induced AA models, while its overexpression inhibited the development of aneurysms. Mechanistically, ANK deficiency in VSMCs caused abnormal cytosolic accumulation of citrate, which was cleaved into acetyl coenzyme A and thus intensified histone acetylation at H3K23, H3K27, and H4K5. Cleavage under target and tagmentation analysis further identified that ANK deficiency-induced histone acetylation activated the transcription of inflammatory genes in VSMCs and thus promoted a citrate-related proinflammatory VSMC phenotype during aneurysm diseases. Accordingly, suppressing citrate cleavage to acetyl coenzyme A downregulated inflammatory gene expression in VSMCs and restricted ANK deficiency-aggravated AA formation. CONCLUSIONS Our studies define the pathogenic role of ANK deficiency-induced cytosolic citrate accumulation in AA pathogenesis and an undescribed citrate-related proinflammatory VSMC phenotype. Targeting ANK-mediated citrate transport may emerge as a novel diagnostic and therapeutic strategy in AA.
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MESH Headings
- Animals
- Mice
- Citric Acid/metabolism
- Humans
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Mice, Knockout
- Aortic Aneurysm/metabolism
- Aortic Aneurysm/genetics
- Aortic Aneurysm/pathology
- Aortic Aneurysm/etiology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Mice, Inbred C57BL
- Cytosol/metabolism
- Male
- Cells, Cultured
- Acetylation
- Acetyl Coenzyme A/metabolism
- Disease Models, Animal
- Histones/metabolism
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Affiliation(s)
- Hao Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Zhiqing Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Liu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China (L.Y.)
| | - Lin He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Hao Liu
- Department of Cardiovascular Surgery, Beijing Aortic Disease Center, Beijing Anzhen Hospital, Capital Medical University, China (H.L., Q.X., J.Z.)
| | - Shiyu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Qinfeng Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yanjie Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Wenqiang Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yiran Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Ze Gong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
- Hwamei College of Life and Health Sciences, Zhejiang Wanli University, Ningbo, China (Z.G.)
| | - Yicong Shen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xueyuan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jiaqi Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Fang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Li Li
- Department of Pathology, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (L.L.)
| | - Junming Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Luyang Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
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Zhu J, Meganathan I, MacAruthur R, Kassiri Z. Inflammation in Abdominal Aortic Aneurysm: Cause or Comorbidity? Can J Cardiol 2024; 40:2378-2391. [PMID: 39181326 DOI: 10.1016/j.cjca.2024.08.274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 08/27/2024] Open
Abstract
Aortic aneurysm is a potentially deadly disease. It is chronic degeneration of the aortic wall that involves an inflammatory response and the immune system, aberrant remodelling of the extracellular matrix, and maladaptive transformation of the aortic cells. This review article focuses on the role of the inflammatory cells in abdominal aortic aneurysm. Studies in human aneurysmal specimens and animal models have identified various inflammatory cell types that could contribute to formation or expansion of aneurysms. These include the commonly studied leukocytes (neutrophils and macrophages) as well as the less commonly explored natural killer cells, dendritic cells, T cells, and B cells. Despite the well-demonstrated contribution of inflammatory cells and the related signalling pathways to development and expansion of aneurysms, anti-inflammatory therapy approaches have demonstrated limitations and may require additional considerations such as a combinational approach in targeting multiple pathways for significant beneficial outcomes.
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Affiliation(s)
- Jiechun Zhu
- Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Ilamaran Meganathan
- Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Roderick MacAruthur
- Department of Cardiac Surgery, Mazankowski Alberta Heart Institute, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Zamaneh Kassiri
- Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
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5
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Galkina SI, Fedorova NV, Golenkina EA, Ksenofontov AL, Serebryakova MV, Kordyukova LV, Stadnichuk VI, Baratova LA, Sud'ina GF. Differential effects of angiotensin II and aldosterone on human neutrophil adhesion and concomitant secretion of proteins, free amino acids and reactive oxygen and nitrogen species. Int Immunopharmacol 2024; 139:112687. [PMID: 39018693 DOI: 10.1016/j.intimp.2024.112687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.
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Affiliation(s)
- Svetlana I Galkina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
| | - Natalia V Fedorova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Ekaterina A Golenkina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Alexander L Ksenofontov
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Marina V Serebryakova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Larisa V Kordyukova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | | | - Ludmila A Baratova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Galina F Sud'ina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
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Chen J, Hu L, Liu Z. Medical treatments for abdominal aortic aneurysm: an overview of clinical trials. Expert Opin Investig Drugs 2024; 33:979-992. [PMID: 38978286 DOI: 10.1080/13543784.2024.2377747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 07/04/2024] [Indexed: 07/10/2024]
Abstract
INTRODUCTION Abdominal aortic aneurysm is a progressive, segmental, abdominal aortic dilation associated with a high mortality rate. Abdominal aortic aneurysms with diameters larger than 55 mm are associated with a high risk of rupture, and the most effective treatment options are surgical repair. Close observation and lifestyle adjustments are recommended for smaller abdominal aortic aneurysms with lower rupture risk. The development of medical therapies that limit or prevent the progression, expansion, and eventual rupture of abdominal aortic aneurysms remains an unmet clinical need. AREAS COVERED This review provides an overview of completed and ongoing clinical trials examining the efficacies of various drug classes, including antibiotics, antihypertensive drugs, hypolipidemic drugs, hypoglycemic drugs, and other potential therapies for abdominal aortic aneurysms. A search of PubMed, Web of Science, Clinical Trials, and another six clinical trial registries was conducted in January 2024. EXPERT OPINION None of the drugs have enough evidence to indicate that they can effectively inhibit the dilation of abdominal aortic aneurysm. More clinical trial data is required to support the efficacy of propranolol. Future research should also explore different drug delivery mechanisms, such as nanoparticles, to elevate drug concentration at the aneurysm wall.
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Affiliation(s)
- Jinyi Chen
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lanting Hu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenjie Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Chen Y, Lin S, Ding M. Letter by Chen et al Regarding Article, "Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration". Circulation 2024; 149:e1194. [PMID: 38768275 DOI: 10.1161/circulationaha.123.068129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Affiliation(s)
- Yunan Chen
- Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China. Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Shaanxi, China
| | - Sixiang Lin
- Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China. Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Shaanxi, China
| | - Mingge Ding
- Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China. Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Shaanxi, China
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Matoc I, Kasa K, Kasumović A, Prpić A, Vukojević A, Zrinšćak O, Škunca Herman J, Doko Mandić B, Sabol I, Iveković R, Vatavuk Z. One Incremental Stride for Doxycycline, One Substantial Advancement for Thyroid Eye Disease. Diagnostics (Basel) 2024; 14:791. [PMID: 38667437 PMCID: PMC11049125 DOI: 10.3390/diagnostics14080791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/15/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
The aim of this study is to assess the effectiveness of a 12-week doxycycline treatment for thyroid eye disease (TED), an autoimmune condition associated with thyroid dysfunction. In this randomized controlled clinical trial, 82 patients were randomly assigned at a 1:1 ratio to receive doxycycline (50 mg) or to undergo no treatment. Various metrics, including margin reflex distance (MRD1 and MRD2), eyelid aperture, levator muscle function, lagophthalmos, proptosis, ocular motility, diplopia, and Graves' ophthalmopathy-specific quality-of-life (GO-QOL) scale scoring were assessed. Exclusion criteria were uncontrolled systemic diseases, tetracycline allergies, pregnancy, lactation, or age below 18. The mean age was 51.6 years (SD), 87.8% of participants were female, and all were Caucasians. By week 12, the doxycycline group exhibited a significant improvement rate based on MRD2 (from 4 to 15 participants with physiological findings), clinical activity score (from 7 to 35 participants with non-active disease), and GO-QOL (from 51.22% to 70.73% of participants with a good life quality). Doxycycline showcased anti-inflammatory and immunomodulatory effects in treating TED, suggesting its potential efficacy for TED and other orbit inflammatory conditions. However, these results warrant further validation through future research involving extended follow-up periods and larger cohorts.
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Affiliation(s)
- Ines Matoc
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Kim Kasa
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Armin Kasumović
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Ante Prpić
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Ante Vukojević
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Ognjen Zrinšćak
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Jelena Škunca Herman
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Blanka Doko Mandić
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Ivan Sabol
- Division of Molecular Medicine, Ruđer Bošković Institute (RBI), 10000 Zagreb, Croatia;
| | - Renata Iveković
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
| | - Zoran Vatavuk
- Ophthalmology Department, Sestre milosrdnice Zagreb UHC, 10000 Zagreb, Croatia; (I.M.); (K.K.); (A.K.); (A.P.); (A.V.); (O.Z.); (B.D.M.); (R.I.); (Z.V.)
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Yoon JA, Ahmad MM, Syed MN, Ahmad MN, Hussaini SF, Muhammad MN, Pir SHA, Khandheria BK, Tajik AJ, Ammar KA. Refining the upper limit of normal for the ascending aorta: In search of optimal criteria -- a large database study of normal individuals. Vascular 2024; 32:254-261. [PMID: 36412136 DOI: 10.1177/17085381221140171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
OBJECTIVES The cutoff for dilated mid-ascending aorta (mAA) is controversial and has several definitions. The present study was carried out to determine the prevalence of mAA dilation based on published definitions and to identify the optimal cutoff. METHODS Echocardiographic studies of patients >15 years of age performed at a large tertiary care center over 4 years, n = 49,330, were retrospectively evaluated. Leading-edge-to-leading-edge technique was used to measure the mAA in diastole. Several cutoff criteria were included. In addition, we defined normals in our database as those who, after 28 causes of dilated aorta were excluded, were normal both clinically and echocardiographically (n = 2334). RESULTS The mean age was 64.2 ± 17.1 years, and 31.5% were men. The prevalence of dilated mAA based on absolute criteria with sex stratification varied between 17% and 23% and based on relative criteria (to age, body surface area, and sex) varied between 6% and 11%. It further decreased to 7.6% on the addition of narrow age stratification (10 year intervals) performed on normals in our database. The multivariate adjusted R2 (for variation in mAA diameter) was 0.25 for age, decreasing to 0.12 for weight and 0.07 for sex and height. CONCLUSIONS The lowest prevalence of 7.6% probably represents the optimal cutoff for dilated mAA because it includes age, which explains most of the variation in mAA, in narrow (10 year) intervals only performed in our normals, which represents the largest sample size to date.
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Affiliation(s)
- Ji Ae Yoon
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Mirza Mujadil Ahmad
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Muhammad Nabeel Syed
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Mirza Nubair Ahmad
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Sharmeen Fatima Hussaini
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Mustafa Noor Muhammad
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Syed Haris A Pir
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Bijoy K Khandheria
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - A Jamil Tajik
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
| | - Khawaja Afzal Ammar
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Advocate Aurora Health, Milwaukee, WI, USA
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10
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Irqsusi M, Dong LA, Rodepeter FR, Ramzan R, Talipov I, Ghazy T, Günther M, Vogt S, Rastan AJ. The Role of Matrix Metalloproteinases in Thoracic Aortic Disease: Are They Indicators for the Pathogenesis of Dissections? Biomedicines 2024; 12:619. [PMID: 38540232 PMCID: PMC10967891 DOI: 10.3390/biomedicines12030619] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/26/2024] [Accepted: 03/06/2024] [Indexed: 04/16/2025] Open
Abstract
The pathogenesis of aortic aneurysm and dissection continues to be under discussion. Extracellular matrix (ECM) remodeling processes in the aortic wall are hypothesized to be involved in the development of the disorders. Therefore, in a histological study, we investigated the expression of metalloproteases 1 and 9 (MMP1 and MMP9) and their inhibitors (TIMP 1 and TIMP 2) in cardiac surgery patients. In parallel, we studied the aortic roots by echocardiography. Clinical reports of 111 patients (30 women and 81 men) who suffered from aortic aneurysms and aortic dissection were evaluated and studied by transesophageal echocardiography. Seven patients who had coronary heart disease served as "healthy controls". All patients underwent the necessary surgical procedure according to the diagnosed aortic disease in the period from 2007 to 2015. A tissue sample of the aortic biopsies was collected from each patient during surgery. Immunohistochemical staining was performed for MMP1 and MMP9 and TIMP1 and TIMP2 as well. Vascularization was monitored by a CD 31 antibody. In direct comparison, the expressions are not homogeneous. We found the smallest changes in the intima area at all. TIMP 1 and TIMP 2 distribution increases from the lumen of the vessel outward in the wall layers of the aorta. In the case of arteriosclerotic changes, intima had a capillarization, but not in the media. An opposite pattern was found in the dissected aortas. There are differences in the vascularization between the aneurysm and dissection and the different layers, respectively. A different remodeling process of the ECM in comparison to the vascular layers must be hypothesized. Reading the patterns of staining and with regard to the known inhibitory effect of MMP9 on ECM remodeling, but especially TIMP 2 on neoangiogenesis, disturbed nutrition, and dysfunctional vasa vasorum remodeling must be assumed as causes of dissection.
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11
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Yap C, Wanga S, Wüst RCI, van Os BW, Pijls MME, Keijzer S, van Zanten E, Koolbergen DR, Driessen AHG, Balm R, Yeung KK, de Vries CJM, Houtkooper RH, Lindeman JHN, de Waard V. Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells. Vascul Pharmacol 2024; 154:107279. [PMID: 38272196 DOI: 10.1016/j.vph.2024.107279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/29/2023] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.
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Affiliation(s)
- Carmen Yap
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Shaynah Wanga
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Cardiology, Meibergdreef 9, Amsterdam, the Netherlands
| | - Rob C I Wüst
- Amsterdam UMC location Vrije Universiteit Amsterdam, Behavioural and Movement Sciences, Myology, Boelelaan 1117, Amsterdam, the Netherlands
| | - Bram W van Os
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands
| | - Maud M E Pijls
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands
| | - Sofie Keijzer
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands
| | - Eva van Zanten
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands
| | - David R Koolbergen
- Amsterdam UMC location University of Amsterdam, Cardiothoracic Surgery, Meibergdreef 9, Amsterdam, the Netherlands
| | - Antoine H G Driessen
- Amsterdam UMC location University of Amsterdam, Cardiothoracic Surgery, Meibergdreef 9, Amsterdam, the Netherlands
| | - Ron Balm
- Amsterdam UMC location University of Amsterdam, Vascular Surgery, Meibergdreef 9, Amsterdam, the Netherlands
| | - Kak Khee Yeung
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Vascular Surgery, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, De Boelelaan 1117, Amsterdam, Netherlands
| | - Carlie J M de Vries
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Riekelt H Houtkooper
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology, and Metabolism, Amsterdam, the Netherlands
| | - Jan H N Lindeman
- Leiden University Medical Center, Vascular Surgery, Leiden, the Netherlands
| | - Vivian de Waard
- Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
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12
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Liu D, Billington CJ, Raja N, Wong ZC, Levin MD, Resch W, Alba C, Hupalo DN, Biamino E, Bedeschi MF, Digilio MC, Squeo GM, Villa R, Parrish PCR, Knutsen RH, Osgood S, Freeman JA, Dalgard CL, Merla G, Pober BR, Mervis CB, Roberts AE, Morris CA, Osborne LR, Kozel BA. Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome. J Am Heart Assoc 2024; 13:e031377. [PMID: 38293922 PMCID: PMC11056152 DOI: 10.1161/jaha.123.031377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/28/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
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Affiliation(s)
- Delong Liu
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Charles J. Billington
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
- Department of PediatricsUniversity of MinnesotaMinneapolisMN
| | - Neelam Raja
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Zoe C. Wong
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Mark D. Levin
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Wulfgang Resch
- The High Performance Computing FacilityCenter for Information Technology, National Institutes of HealthBethesdaMD
| | - Camille Alba
- Henry M Jackson Foundation for the Advancement of Military MedicineBethesdaMD
| | - Daniel N. Hupalo
- Henry M Jackson Foundation for the Advancement of Military MedicineBethesdaMD
| | | | | | | | - Gabriella Maria Squeo
- Laboratory of Regulatory and Functional GenomicsFondazione IRCCS Casa Sollievo della SofferenzaSan Giovanni Rotondo (Foggia)Italy
| | - Roberta Villa
- Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Medical Genetic UnitMilanItaly
| | - Pheobe C. R. Parrish
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
- Department of Genome SciencesUniversity of WashingtonSeattleWA
| | - Russell H. Knutsen
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Sharon Osgood
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Joy A. Freeman
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
| | - Clifton L. Dalgard
- Department of Anatomy, Physiology and Genetics, School of Medicinethe Uniformed Services University of the Health SciencesBethesdaMD
| | - Giuseppe Merla
- Laboratory of Regulatory and Functional GenomicsFondazione IRCCS Casa Sollievo della SofferenzaSan Giovanni Rotondo (Foggia)Italy
- Department of Molecular Medicine and Medical BiotechnologyUniversity of Naples Federico IINaplesItaly
| | - Barbara R. Pober
- Section of Genetics, Department of PediatricsMassachusetts General HospitalBostonMA
| | - Carolyn B. Mervis
- Department of Psychological and Brain SciencesUniversity of LouisvilleLouisvilleKY
| | - Amy E. Roberts
- Department of Cardiology and Division of Genetics and Genomics, Department of PediatricsBoston Children’s HospitalBostonMA
| | - Colleen A. Morris
- Department of PediatricsKirk Kerkorian School of Medicine at UNLVLas VegasNV
| | - Lucy R. Osborne
- Departments of Medicine and Molecular GeneticsUniversity of TorontoCanada
| | - Beth A. Kozel
- National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMD
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13
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Han Q, Qiao L, Yin L, Sui X, Shao W, Wang Q. The effect of exercise training intervention for patients with abdominal aortic aneurysm on cardiovascular and cardiorespiratory variables: an updated meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2024; 24:80. [PMID: 38291355 PMCID: PMC10829311 DOI: 10.1186/s12872-024-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/22/2024] [Indexed: 02/01/2024] Open
Abstract
OBJECTIVE The purpose of this meta-analysis was to evaluate the effect of exercise training intervention in patients with abdominal aortic aneurysm (AAA). METHODS Eight randomized controlled trials (RCTs) that recruited 588 AAA patients were extracted using 4 databases (PubMed, Embase, Wanfang Data, and Cochrane Library). Physiological and biochemistry parameters that included in this study are high-sensitivity C-reactive protein (hs-CRP), respiratory peak oxygen uptake rate (VO2peak), triglyceride (TG), total cholesterol (TC), anaerobic threshold (AT), the diameter of AAA, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), and matrix metalloproteinase-9 (MMP-9). Standard mean difference (SMD) was used to assess the between group effect. RESULTS This meta-analysis was synthesized with findings from RCTs and found that hs-CRP (SMD, - 0.56 mg/dL; 95% CI: - 0.90 to 0.22; P = 0.001), VO2peak (SMD, 0.4 mL/kg/min; 95% CI, 0.21 to 0.60; P < 0.001), TG (SMD, - 0.39 mg/dL; 95% CI: - 0.02 to 0.77; P = 0.04), and AT (SMD, 0.75 mL/kg/min; 95% CI, 0.54 to 0.96; P < 0.001) were significantly improved in the exercise groups, while the size of AAA (SMD, - 0.15; 95% CI: - 0.36 to 0.06; P = 0.15), TC (SMD, 0.16 mg/dL; 95% CI: - 0.10 to 0.42; P = 0.23), HDL/LDL ratio (SMD, - 0.06; 95% CI: - 0.32 to 0.20; P = 0.64), HDL (SMD, - 0.09; 95% CI: - 0.39 to 0.20; P = 0.54), LDL (SMD, 0.08; 95% CI: - 0.21 to 0.38; P = 0.59), and MMP-9 (SMD, - 0.23 mg/dL; 95% CI: - 0.53 to 0.06; P = 0.12) did not differ in the exercise groups compared with the controls. CONCLUSION Exercise intervention improved some of the CVD risk factors but not all, hs-CRP, VO2peak and AT were significantly improved after exercise intervention, while, changes of MMP-9, the size of AAA, and the overall lipids profile were not. Exercise intervention provides an additional solution for improving cardiorespiratory capacity and health status among AAA patients, and might lead to a delay of AAA progression.
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Affiliation(s)
- Qi Han
- Sports Nutrition Center, National Institute of Sports Medicine, Beijing, 100029, China
- Beijing Sport University, Beijing, 100084, China
| | - Li Qiao
- Beijing Competitor Sports Nutrition Research Institute, Beijing, 100029, China
| | - Li Yin
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310020, China
- Department of Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Xuemei Sui
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA
| | - Wenjuan Shao
- Beijing Sport University, Beijing, 100084, China
- Minzu University of China, Beijing, 100081, China
| | - Qirong Wang
- Sports Nutrition Center, National Institute of Sports Medicine, Beijing, 100029, China.
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14
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Wang Q, Chen G, Qi Z, Zeng Y, Tan L, Tang H. Global research status analysis of the association between aortic aneurysm and inflammation: a bibliometric analysis from 1999 to 2023. Front Cardiovasc Med 2023; 10:1260935. [PMID: 38111889 PMCID: PMC10725951 DOI: 10.3389/fcvm.2023.1260935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/20/2023] [Indexed: 12/20/2023] Open
Abstract
Background Aortic aneurysm is a chronic arterial disease that can lead to aortic rupture, causing severe complications and life-threatening risks for patients, and it is one of the common causes of death among the elderly. Increasing evidence suggests that inflammation plays an important role in the progression of aortic aneurysm. However, there is a lack of literature-based quantitative analysis in this field. Methods Up to March 30, 2023, we collected 3,993 articles related to aortic aneurysm and inflammation from the Web of Science Core Collection (WoSCC) database for bibliometric analysis. The collected literature data were subjected to visual analysis of regional distribution, institutions, authors, keywords, and other information using tools such as CiteSpace, VOSviewer, the R package "bibliometric," and online platforms. Results The number of publications in this research field has been steadily increasing each year, with the United States and China being the main contributing countries. Harvard University in the United States emerged as the most active and influential research institution in this field. Jonathan Golledge and Peter Libby were identified as the authors with the highest publication output and academic impact, respectively. Researchers in this field tend to publish their findings in influential journals such as the Journal of Vascular Surgery and Arteriosclerosis Thrombosis and Vascular Biology. "Abdominal aortic aneurysm," "giant cell arteritis," "arterial stiffness," and "smooth muscle cells" were identified as the hottest topics in the field of aortic aneurysm and inflammation. In terms of keyword co-occurrence analysis, "Clinical relevant studies of AA" (red), "Inflammatory activation" (green), "Inflammatory mechanisms related to pathogenesis" (dark blue), "Cytokines" (yellow), "Risk factors" (purple), and "Pathological changes in vascular wall" (cyan) formed the major research framework in this field. "Inflammation-related pathogenesis" and "inflammation activation" have emerged as recent hot research directions, with "monocytes," "progression," and "proliferation" being the prominent topics. Conclusion This study provides a comprehensive analysis of the knowledge network framework and research hotspots in the field of aortic aneurysm and inflammation through a literature-based quantitative approach. It offers valuable insights to guide scholars in identifying meaningful research directions in this field.
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Affiliation(s)
- Qiuguo Wang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guihuan Chen
- Department of Anesthesiology, Reproductive and Genetic Hospital of Citic-Xiangya, Changsha, China
| | - Zhen Qi
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yifan Zeng
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling Tan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Tang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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15
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Chang H, Kuo CF, Yu TS, Ke LY, Hung CL, Tsai SY. Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study. J Transl Med 2023; 21:804. [PMID: 37951920 PMCID: PMC10638797 DOI: 10.1186/s12967-023-04636-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan's National Health Insurance Research Database. METHODS From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made. RESULTS The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person-years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47-1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05). CONCLUSION Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.
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Affiliation(s)
- Hsun Chang
- Division of Infectious Diseases, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chien-Feng Kuo
- Division of Infectious Diseases, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 252, Taiwan
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD, 21205, USA
| | - Teng-Shun Yu
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Liang-Yin Ke
- Medical Laboratory Science & Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Lieh Hung
- Division of Cardiology, Departments of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan
| | - Shin-Yi Tsai
- Department of Medicine, MacKay Medical College, New Taipei City, 252, Taiwan.
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan.
- Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei, 104, Taiwan.
- Institute of Long-Term Care, MacKay Medical College, New Taipei City, Taiwan.
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16
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Atkinson G, Bianco R, Di Gregoli K, Johnson JL. The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms. Front Cardiovasc Med 2023; 10:1248561. [PMID: 37799778 PMCID: PMC10549934 DOI: 10.3389/fcvm.2023.1248561] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/07/2023] [Indexed: 10/07/2023] Open
Abstract
Abdominal aortic aneurysms (AAAs) account for up to 8% of deaths in men aged 65 years and over and 2.2% of women. Patients with AAAs often have atherosclerosis, and intimal atherosclerosis is generally present in AAAs. Accordingly, AAAs are considered a form of atherosclerosis and are frequently referred to as atherosclerotic aneurysms. Pathological observations advocate inflammatory cell infiltration alongside adverse extracellular matrix degradation as key contributing factors to the formation of human atherosclerotic AAAs. Therefore, macrophage production of proteolytic enzymes is deemed responsible for the damaging loss of ECM proteins, especially elastin and fibrillar collagens, which characterise AAA progression and rupture. Matrix metalloproteinases (MMPs) and their regulation by tissue inhibitors metalloproteinases (TIMPs) can orchestrate not only ECM remodelling, but also moderate the proliferation, migration, and apoptosis of resident aortic cells, alongside the recruitment and subsequent behaviour of inflammatory cells. Accordingly, MMPs are thought to play a central regulatory role in the development, progression, and eventual rupture of abdominal aortic aneurysms (AAAs). Together, clinical and animal studies have shed light on the complex and often diverse effects MMPs and TIMPs impart during the development of AAAs. This dichotomy is underlined from evidence utilising broad-spectrum MMP inhibition in animal models and clinical trials which have failed to provide consistent protection from AAA progression, although more encouraging results have been observed through deployment of selective inhibitors. This review provides a summary of the supporting evidence connecting the contribution of individual MMPs to AAA development, progression, and eventual rupture. Topics discussed include structural, functional, and cell-specific diversity of MMP members; evidence from animal models of AAA and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the advances in identifying aberrant MMP activity. As evidenced, our developing understanding of the multifaceted roles individual MMPs perform during the progression and rupture of AAAs, should motivate clinical trials assessing the therapeutic potential of selective MMP inhibitors, which could restrict AAA-related morbidity and mortality worldwide.
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Affiliation(s)
| | | | | | - Jason L. Johnson
- Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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17
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Costantini A, Guasto A, Cormier-Daire V. TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature. Annu Rev Genomics Hum Genet 2023; 24:225-253. [PMID: 37624666 DOI: 10.1146/annurev-genom-120922-094107] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2023]
Abstract
The transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways play a pivotal role in bone development and skeletal health. More than 30 different types of skeletal dysplasia are now known to be caused by pathogenic variants in genes that belong to the TGF-β superfamily and/or regulate TGF-β/BMP bioavailability. This review describes the latest advances in skeletal dysplasia that is due to impaired TGF-β/BMP signaling and results in short stature (acromelic dysplasia and cardiospondylocarpofacial syndrome) or tall stature (Marfan syndrome). We thoroughly describe the clinical features of the patients, the underlying genetic findings, and the pathomolecular mechanisms leading to disease, which have been investigated mainly using patient-derived skin fibroblasts and mouse models. Although no pharmacological treatment is yet available for skeletal dysplasia due to impaired TGF-β/BMP signaling, in recent years advances in the use of drugs targeting TGF-β have been made, and we also discuss these advances.
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Affiliation(s)
- Alice Costantini
- Paris Cité University, INSERM UMR 1163, Institut Imagine, Paris, France; , ,
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Alessandra Guasto
- Paris Cité University, INSERM UMR 1163, Institut Imagine, Paris, France; , ,
| | - Valérie Cormier-Daire
- Paris Cité University, INSERM UMR 1163, Institut Imagine, Paris, France; , ,
- Reference Center for Skeletal Dysplasia, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
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18
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Gong W, Tian Y, Li L. T cells in abdominal aortic aneurysm: immunomodulation and clinical application. Front Immunol 2023; 14:1240132. [PMID: 37662948 PMCID: PMC10471798 DOI: 10.3389/fimmu.2023.1240132] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration, extracellular matrix (ECM) degradation, and vascular smooth muscle cell (SMC) dysfunction. The inflammatory cells involved in AAA mainly include immune cells including macrophages, neutrophils, T-lymphocytes and B lymphocytes and endothelial cells. As the blood vessel wall expands, more and more lymphocytes infiltrate into the outer membrane. It was found that more than 50% of lymphocytes in AAA tissues were CD3+ T cells, including CD4+, CD8+T cells, γδ T cells and regulatory T cells (Tregs). Due to the important role of T cells in inflammatory response, an increasing number of researchers have paid attention to the role of T cells in AAA and dug into the relevant mechanism. Therefore, this paper focuses on reviewing the immunoregulatory role of T cells in AAA and their role in immunotherapy, seeking potential targets for immunotherapy and putting forward future research directions.
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Affiliation(s)
| | | | - Lei Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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19
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Puertas-Umbert L, Almendra-Pegueros R, Jiménez-Altayó F, Sirvent M, Galán M, Martínez-González J, Rodríguez C. Novel pharmacological approaches in abdominal aortic aneurysm. Clin Sci (Lond) 2023; 137:1167-1194. [PMID: 37559446 PMCID: PMC10415166 DOI: 10.1042/cs20220795] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/05/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.
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Affiliation(s)
- Lídia Puertas-Umbert
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
| | | | - Francesc Jiménez-Altayó
- Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marc Sirvent
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Angiología y Cirugía Vascular del Hospital Universitari General de Granollers, Granollers, Barcelona, Spain
| | - María Galán
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain
| | - José Martínez-González
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain
| | - Cristina Rodríguez
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
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20
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Golledge J, Thanigaimani S, Powell JT, Tsao PS. Pathogenesis and management of abdominal aortic aneurysm. Eur Heart J 2023:ehad386. [PMID: 37387260 PMCID: PMC10393073 DOI: 10.1093/eurheartj/ehad386] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/16/2023] [Accepted: 05/29/2023] [Indexed: 07/01/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have been limited by small sample sizes, limited drug adherence, poor participant retention, and over-optimistic AAA growth reduction targets. Data from some large observational cohorts suggest that blood pressure reduction, particularly by angiotensin-converting enzyme inhibitors, could limit aneurysm rupture, but this has not been evaluated in randomized trials. Some observational studies suggest metformin may limit AAA growth, and this is currently being tested in randomized trials. In conclusion, no drug therapy has been shown to convincingly limit AAA growth in randomized controlled trials. Further large prospective studies on other targets are needed.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Australian Institute of Tropical Health and Medicine, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Department of Vascular and Endovascular Surgery, Townsville University Hospital, 100 Angus Smith Drive, Douglas, QLD, Australia
| | - Shivshankar Thanigaimani
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Australian Institute of Tropical Health and Medicine, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
| | - Janet T Powell
- Department of Surgery & Cancer, Imperial College London, Fulham Palace Road, London, UK
| | - Phil S Tsao
- Department of Cardiovascular Medicine, Stanford University, 450 Serra Mall, Stanford, CA, USA
- VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, USA
- Stanford Cardiovascular Institute, Stanford University, 450 Serra Mall, Stanford, CA, USA
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21
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Tian Y, Li X, Bai C, Yang Z, Zhang L, Luo J, Zhang W. lncRNA MIR503HG Targets miR-191-5p/PLCD1 Axis and Negatively Modulates Apoptosis, Extracellular Matrix Disruption, and Inflammation in Abdominal Aortic Aneurysm. Mediators Inflamm 2023; 2023:4003618. [PMID: 37228901 PMCID: PMC10205412 DOI: 10.1155/2023/4003618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 11/09/2022] [Accepted: 04/05/2023] [Indexed: 05/27/2023] Open
Abstract
As the most prevalent subtype of aortic aneurysm, abdominal aortic aneurysm (AAA) features the apoptosis, extracellular matrix (ECM) disruption, and inflammation response of vascular smooth muscle cells (VSMCs). Noncoding RNAs (ncRNAs) are crucial factors in AAA progression, while the investigations have not been fully explained. miR-191-5p upregulation is found in aortic aneurysm. However, its role in AAA has not been addressed. This research purposed to excavate the possible and associated molecular axis of miR-191-5p in AAA. In our study, miR-191-5p level was detected to be high in the tissues from AAA patients in comparison with the control group. After miR-191-5p expression was enhanced, cell viability was repressed, cell apoptosis was boosted, and ECM disruption and the inflammation response were fortified. Furthermore, the relationship among MIR503HG, miR-191-5p, and phospholipase C delta 1 (PLCD1) in VSMCs was disclosed via mechanism assays. Decreased MIR503HG lacked the inhibition on miR-191-5p targeting PLCD1, resulting in downregulation of PLCD1, which facilitated the progression of AAA. Thus, targeting MIR503HG/miR-191-5p/PLCD1 pathway will provide an additional method for the cure of AAA patients.
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Affiliation(s)
- Ye Tian
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Xinxi Li
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Chao Bai
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Zhenwei Yang
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Lei Zhang
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Jun Luo
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
| | - Wenbin Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000 Xinjiang Uygur Autonomous Region, China
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22
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Cao M, Yao S, Zhu X, Ong MTY, Yung PSH, Jiang Y. Doxycycline Promotes Graft Healing and Attenuates Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Reconstruction in a Rat Model. Am J Sports Med 2023; 51:461-475. [PMID: 36645043 DOI: 10.1177/03635465221145015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Doxycycline (Doxy) has been shown to facilitate tendon healing by reducing on-site matrix metalloproteinase (MMP) activity, but its effect on graft healing after anterior cruciate ligament reconstruction (ACLR) has not been investigated, and the therapeutic effect of Doxy in preventing ACLR-induced posttraumatic osteoarthritis (PTOA) is unclear. HYPOTHESIS Doxy promotes graft healing and alleviates the progression of PTOA after ACLR. STUDY DESIGN Controlled laboratory study. METHODS Sprague Dawley rats (n = 74; age, 12-13 weeks; male) that underwent ACLR were divided into untreated control and Doxy treatment (50 mg/kg/d orally until sacrifice) groups. At 2 and 6 weeks after surgery, graft healing was assessed by biomechanical testing, histology, immunohistochemical staining, and micro-computed tomography (μCT). The progression of PTOA was evaluated at 6 weeks by histology, the Mankin score, and immunofluorescence staining of the tibial plateau, and osteophyte formation was evaluated by μCT. Hindlimb weight distribution was evaluated at 6 weeks, and gait patterns were evaluated at 2 and 6 weeks. Intra-articular MMP activity was evaluated at 6 weeks in vivo using an MMP-activatable near-infrared fluorescent probe. RESULTS Graft healing was enhanced by Doxy treatment, and the ultimate failure load (P = .002) and stiffness of the graft (P = .007) were significantly higher in the Doxy group at week 2. Bone mineral density and bone volume/total volume for both the tibial and the femoral tunnels at week 6 in the Doxy group were significantly higher compared with in the control group (P < .05). The overall graft healing scores were significantly higher in the Doxy group. Doxy treatment enhanced graft integration, intratunnel graft integrity, and collagen birefringence; more collagen types 1 and 10 and less MMP-13 were found at the graft-bone interface. At week 6, the Doxy group had a lower modified Mankin score (P = .033) and showed fewer MMP 13-positive chondrocytes at the articular cartilage surface (P = .002), indicating moderate joint cartilage damage. μCT revealed less osteophyte formation, and gait analysis revealed more symmetric weightbearing and gait patterns, after Doxy treatment at week 6 (P < .05). In vivo imaging with the near-infrared fluorescent probe identified significantly lower intra-articular MMP activity in the Doxy group at week 6 (P = .016). CONCLUSION The oral administration of Doxy was able to synchronously promote graft healing and attenuate PTOA in an ACLR rat model. CLINICAL RELEVANCE Our results indicated that Doxy, a widely used drug, is potentially beneficial to patients after ACLR.
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Affiliation(s)
- Mingde Cao
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
| | - Shiyi Yao
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
| | - Xiaobo Zhu
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China.,Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Michael T Y Ong
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
| | - Patrick S H Yung
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China.,Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yangzi Jiang
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China.,Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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23
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Peng F, Xia J, Niu H, Feng X, Zheng T, He X, Xu B, Chen X, Xu P, Zhang H, Chen J, Tong X, Bai X, Li Z, Duan Y, Sui B, Zhao X, Liu A. Systemic immune-inflammation index is associated with aneurysmal wall enhancement in unruptured intracranial fusiform aneurysms. Front Immunol 2023; 14:1106459. [PMID: 36776878 PMCID: PMC9911448 DOI: 10.3389/fimmu.2023.1106459] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/13/2023] [Indexed: 01/28/2023] Open
Abstract
Introduction Inflammation plays a key role in the progression of intracranial aneurysms. Aneurysmal wall enhancement (AWE) correlates well with inflammatory processes in the aneurysmal wall. Understanding the potential associations between blood inflammatory indices and AWE may aid in the further understanding of intracranial aneurysm pathophysiology. Methods We retrospectively reviewed 122 patients with intracranial fusiform aneurysms (IFAs) who underwent both high-resolution magnetic resonance imaging and blood laboratory tests. AWE was defined as a contrast ratio of the signal intensity of the aneurysmal wall to that of the pituitary stalk ≥ 0.90. The systemic immune-inflammation (SII) index (neutrophils × platelets/lymphocytes) was calculated from laboratory data and dichotomized based on whether or not the IFA had AWE. Aneurysmal symptoms were defined as sentinel headache or oculomotor nerve palsy. Multivariable logistic regression and receiver operating characteristic curve analyses were performed to determine how well the SII index was able to predict AWE and aneurysmal symptoms. Spearman's correlation coefficients were used to explore the potential associations between variables. Results This study included 95 patients, of whom 24 (25.3%) presented with AWE. After adjusting for baseline differences in neutrophil to lymphocyte ratios, leukocytes, and neutrophils in the multivariable logistic regression analysis, smoking history (P = 0.002), aneurysmal symptoms (P = 0.047), maximum diameter (P = 0.048), and SII index (P = 0.022) all predicted AWE. The SII index (P = 0.038) was the only independent predictor of aneurysmal symptoms. The receiver operating characteristic curve analysis revealed that the SII index was able to accurately distinguish IFAs with AWE (area under the curve = 0.746) and aneurysmal symptoms (area under the curve = 0.739). Discussion An early elevation in the SII index can independently predict AWE in IFAs and is a potential new biomarker for predicting IFA instability.
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Affiliation(s)
- Fei Peng
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jiaxiang Xia
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hao Niu
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xin Feng
- Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianheng Zheng
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, China
| | - Xiaoxin He
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Boya Xu
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xuge Chen
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Peng Xu
- Department of Neurosurgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Hong Zhang
- Operating Room, Heze Municipal Hospital, Heze, Shandong, China
| | - Jigang Chen
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xin Tong
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyan Bai
- Tiantan Neuroimaging Center of Excellence, China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Zhiye Li
- Tiantan Neuroimaging Center of Excellence, China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yonghong Duan
- Department of Neurosurgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Binbin Sui
- Tiantan Neuroimaging Center of Excellence, China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xingquan Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China,*Correspondence: Aihua Liu, ; Xingquan Zhao,
| | - Aihua Liu
- Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China,*Correspondence: Aihua Liu, ; Xingquan Zhao,
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24
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Wu H, Xie C, Wang R, Cheng J, Xu Q, Zhao H. Comparative analysis of thoracic and abdominal aortic aneurysms across the segment and species at the single-cell level. Front Pharmacol 2023; 13:1095757. [PMID: 36703732 PMCID: PMC9871934 DOI: 10.3389/fphar.2022.1095757] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/12/2022] [Indexed: 01/12/2023] Open
Abstract
Introduction: Aortic aneurysm is a life-threatening disease resulted from progressive dilatation of the aorta, which can be subdivided into thoracic and abdominal aortic aneurysms. Sustained subcutaneous angiotensin II infusion can induce aortic aneurysms in mice. However, the relevance of using angiotensin II induction model to study aneurysm disease and the degree of commonality between species remain elusive. Methods: We utilized scRNA-seq to infer aortic cell sub-structures and transcriptional profiles in clinical patient TAAs and AAAs, as well as mouse models of corresponding diseases (Ang II induction) and in healthy mouse aorta. Unbiased comparison between mice and humans explored the possible reasonability and utility of mouse Ang II-induced aortic aneurysm as a model for human aortic aneurysm diseases. Meanwhile, we performed comparative analysis of aortic aneurysms between TAA and AAA in both organisms. Results and Discussion: We demonstrated similarities and differences of changes in the components of human and mouse cell types, and our unbiased comparison between mouse and human identified well conserved subpopulations of SMCs and macrophages. Furthermore, the results of our comparative analyses suggested different biological functions and distinct potential pathogenic genes for thoracic and abdominal aortic aneurysms. MIF and SPP1 signaling networks participated in aortic aneurysm in both organisms. This study maps aortic aneurysm and offers opportunities for future researches to investigate the potential of subpopulations or marker genes as therapy targets.
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Affiliation(s)
- Hong Wu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cheng Xie
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Southwest Medical University, Luzhou, China
| | - Ruilin Wang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Cheng
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Southwest Medical University, Luzhou, China
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,*Correspondence: Qingbo Xu, ; Haige Zhao,
| | - Haige Zhao
- Department of Cardiovascular Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,*Correspondence: Qingbo Xu, ; Haige Zhao,
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25
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Weaver LM, Loftin CD, Zhan CG. Development of pharmacotherapies for abdominal aortic aneurysms. Biomed Pharmacother 2022; 153:113340. [PMID: 35780618 PMCID: PMC9514980 DOI: 10.1016/j.biopha.2022.113340] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 11/23/2022] Open
Abstract
The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.
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Affiliation(s)
- Lauren M Weaver
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
| | - Charles D Loftin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
| | - Chang-Guo Zhan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
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Wang Y, Chuang CY, Hawkins CL, Davies MJ. Activation and Inhibition of Human Matrix Metalloproteinase-9 (MMP9) by HOCl, Myeloperoxidase and Chloramines. Antioxidants (Basel) 2022; 11:antiox11081616. [PMID: 36009335 PMCID: PMC9405048 DOI: 10.3390/antiox11081616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/24/2022] Open
Abstract
Matrix metalloproteinase-9 (MMP9, gelatinase B) plays a key role in the degradation of extracellular-matrix (ECM) proteins in both normal physiology and multiple pathologies, including those linked with inflammation. MMP9 is excreted as an inactive proform (proMMP9) by multiple cells, and particularly neutrophils. The proenzyme undergoes subsequent processing to active forms, either enzymatically (e.g., via plasmin and stromelysin-1/MMP3), or via the oxidation of a cysteine residue in the prodomain (the “cysteine-switch”). Activated leukocytes, including neutrophils, generate O2− and H2O2 and release myeloperoxidase (MPO), which catalyzes hypochlorous acid (HOCl) formation. Here, we examine the reactivity of HOCl and a range of low-molecular-mass and protein chloramines with the pro- and activated forms of MMP9. HOCl and an enzymatic MPO/H2O2/Cl− system were able to generate active MMP9, as determined by fluorescence-activity assays and gel zymography. The inactivation of active MMP9 also occurred at high HOCl concentrations. Low (nM—low μM) concentrations of chloramines formed by the reaction of HOCl with amino acids (taurine, lysine, histidine), serum albumin, ECM proteins (laminin and fibronectin) and basement membrane extracts (but not HEPES chloramines) also activate proMMP9. This activation is diminished by the competitive HOCl-reactive species, methionine. These data indicate that HOCl-mediated oxidation and MMP-mediated ECM degradation are synergistic and interdependent. As previous studies have shown that modified ECM proteins can also stimulate the cellular expression of MMP proteins, these processes may contribute to a vicious cycle of increasing ECM degradation during disease development.
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Affiliation(s)
- Yihe Wang
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Christine Y Chuang
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Clare L Hawkins
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Michael J Davies
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark
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Thanigaimani S, Phie J, Quigley F, Bourke M, Bourke B, Velu R, Jenkins J, Golledge J. Immunosuppressive drugs for nontransplant comorbidities are not associated with abdominal aortic aneurysm growth. JVS Vasc Sci 2022; 3:306-313. [PMID: 36643689 PMCID: PMC9834429 DOI: 10.1016/j.jvssci.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/07/2022] [Accepted: 07/13/2022] [Indexed: 01/18/2023] Open
Abstract
Background In the present study, we examined the association of immunosuppressant drug prescriptions with the growth of small abdominal aortic aneurysms (AAAs). Methods Participants with an AAA measuring between 30 and 50 mm were recruited from four Australian centers. AAA growth was monitored by ultrasound. The immunosuppressant drugs included conventional disease-modifying antirheumatic drugs (eg, methotrexate, sulfasalazine, leflunomide), steroids, hydroxychloroquine, other immunosuppressant drugs (eg, cyclosporine, azacitidine), or a combination of these drugs. Linear mixed effects modeling was performed to examine the independent association of an immunosuppressant prescription with AAA growth. A subanalysis examined the association of steroids with AAA growth. Results Of the 621 patients, 34 (5.3%) had been prescribed at least one (n = 26) or more (n = 8) immunosuppressant drug and had been followed up for a median period of 2.1 years (interquartile range, 1.1-3.5 years), with a median of three ultrasound scans (interquartile range, two to five ultrasound scans). No significant difference was found in AAA growth when stratified by a prescription of immunosuppressant drugs on either unadjusted (mean difference, 0.2 mm/y; 95% confidence interval [CI], -0.4 to 0.7; P = .589) or risk factor-adjusted (mean difference, 0.2 mm/y; 95% CI, -0.3 to 0.7; P = .369) analyses. The findings were similar for the unadjusted (mean difference, 0.0 mm/y; 95% CI, -0.7 to 0.7; P = .980) and risk factor-adjusted (mean difference, 0.1 mm/y; 95% CI, -0.6 to 0.7; P = .886) subanalyses focused on steroid use. Conclusions The results from this study suggest that AAA growth is not affected by immunosuppressant drug prescription. Studies with larger sample sizes are needed before reliable conclusions can be drawn.
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Affiliation(s)
- Shivshankar Thanigaimani
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia,Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia
| | - James Phie
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia,Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia
| | | | - Michael Bourke
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia,Gosford Vascular Services, Gosford, NSW, Australia
| | - Bernie Bourke
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia,Gosford Vascular Services, Gosford, NSW, Australia
| | - Ramesh Velu
- Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, QLD, Australia
| | - Jason Jenkins
- Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia,Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia,Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, QLD, Australia,Correspondence: Jonathan Golledge, MA, FRCS, FRACS, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
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The Detrimental Role of Intraluminal Thrombus Outweighs Protective Advantage in Abdominal Aortic Aneurysm Pathogenesis: The Implications for the Anti-Platelet Therapy. Biomolecules 2022; 12:biom12070942. [PMID: 35883500 PMCID: PMC9313225 DOI: 10.3390/biom12070942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 07/01/2022] [Indexed: 02/01/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is a common cardiovascular disease resulting in morbidity and mortality in older adults due to rupture. Currently, AAA treatment relies entirely on invasive surgical treatments, including open repair and endovascular, which carry risks for small aneurysms (diameter < 55 mm). There is an increasing need for the development of pharmacological intervention for early AAA. Over the last decade, it has been increasingly recognized that intraluminal thrombus (ILT) is involved in the growth, remodeling, and rupture of AAA. ILT has been described as having both biomechanically protective and biochemically destructive properties. Platelets are the second most abundant cells in blood circulation and play an integral role in the formation, expansion, and proteolytic activity of ILT. However, the role of platelets in the ILT-potentiated AAA progression/rupture remains unclear. Researchers are seeking pharmaceutical treatment strategies (e.g., anti-thrombotic/anti-platelet therapies) to prevent ILT formation or expansion in early AAA. In this review, we mainly focus on the following: (a) the formation/deposition of ILT in the progression of AAA; (b) the dual role of ILT in the progression of AAA (protective or detrimental); (c) the function of platelet activity in ILT formation; (d) the application of anti-platelet drugs in AAA. Herein, we present challenges and future work, which may motivate researchers to better explain the potential role of ILT in the pathogenesis of AAA and develop anti-platelet drugs for early AAA.
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Mottis A, Li TY, El Alam G, Rapin A, Katsyuba E, Liaskos D, D'Amico D, Harris NL, Grier MC, Mouchiroud L, Nelson ML, Auwerx J. Tetracycline-induced mitohormesis mediates disease tolerance against influenza. J Clin Invest 2022; 132:151540. [PMID: 35787521 PMCID: PMC9433105 DOI: 10.1172/jci151540] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/01/2022] [Indexed: 11/22/2022] Open
Abstract
Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress on eukaryotic cells. We demonstrate in cell and germ-free mouse models that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the ATF4-mediated integrative stress response and type I interferon (IFN) signaling. To overcome the interferences of tetracyclines with the host microbiome, we identify tetracycline derivatives that have minimal antimicrobial activity, yet retain full capacity to induce the MSR, such as the lead compound, 9-tert-butyl doxycycline (9-TB). The MSR induced by doxycycline (Dox) and 9-TB improves survival and disease tolerance against lethal influenza virus (IFV) infection when given preventively. 9-TB, unlike Dox, did not affect the gut microbiome and also showed encouraging results against IFV when given in a therapeutic setting. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function, and with downregulation of inflammatory and immune gene sets in lungs, liver, and kidneys. Mitohormesis induced by non-antimicrobial tetracyclines and the ensuing IFN response may dampen excessive inflammation and tissue damage during viral infections, opening innovative therapeutic avenues.
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Affiliation(s)
- Adrienne Mottis
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Terytty Y Li
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Gaby El Alam
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Alexis Rapin
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Elena Katsyuba
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - David Liaskos
- EPFL Innovation Park, Nagi Bioscience SA, Ecublens, Switzerland
| | - Davide D'Amico
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Nicola L Harris
- Department of Immunology and Pathology, Monash University, Melbourne, Australia
| | - Mark C Grier
- Echelon Biosciences, Inc., Salt Lake City, United States of America
| | | | - Mark L Nelson
- Echelon Biosciences, Inc., Salt Lake City, United States of America
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Ballester-Servera C, Cañes L, Alonso J, Puertas L, Taurón M, Rodríguez C, Martínez-González J. Nuclear receptor NOR-1 (Neuron-derived Orphan Receptor-1) in pathological vascular remodelling and vascular remodelling. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2022; 34:229-243. [PMID: 35581107 DOI: 10.1016/j.arteri.2022.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 06/15/2023]
Abstract
Vascular cells and their interaction with inflammatory cells and the immune system play a key role in pathological vascular remodeling. A large number of genes and proteins regulated in a coordinated manner by a small number of transcription factors are involved in this process. In recent years, research on a small subfamily of transcription factors, the NR4A subfamily, has had a major impact on our understanding of vascular biology. The NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (NOR-1) receptors are products of early response genes whose expression is induced by multiple pathophysiological and physical stimuli. Their wide distribution in different tissues and cells places them in the control of numerous processes such as cell differentiation, proliferation, survival and apoptosis, as well as inflammation and the metabolism of lipids and carbohydrates. This review analyzes the role of these receptors, particularly NOR-1, in pathological vascular remodeling associated with atherosclerosis, abdominal aortic aneurysm and pulmonary arterial hypertension.
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Affiliation(s)
- Carme Ballester-Servera
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, España; CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, España; Instituto de Investigación Biomédica Sant Pau, Barcelona, España
| | - Laia Cañes
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, España; CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, España
| | - Judith Alonso
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, España; CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, España; Instituto de Investigación Biomédica Sant Pau, Barcelona, España
| | - Lidia Puertas
- Instituto de Investigación Biomédica Sant Pau, Barcelona, España; Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, España
| | - Manel Taurón
- Servicio de Cirugía Cardiovascular, Hospital de la Santa Creu i Sant Pau, Barcelona, España
| | - Cristina Rodríguez
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, España; Instituto de Investigación Biomédica Sant Pau, Barcelona, España; Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, España
| | - José Martínez-González
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, España; CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, España; Instituto de Investigación Biomédica Sant Pau, Barcelona, España.
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Liu Y, Zou L, Tang H, Li J, Liu H, Jiang X, Jiang B, Dong Z, Fu W. Single-Cell Sequencing of Immune Cells in Human Aortic Dissection Tissue Provides Insights Into Immune Cell Heterogeneity. Front Cardiovasc Med 2022; 9:791875. [PMID: 35433892 PMCID: PMC9008490 DOI: 10.3389/fcvm.2022.791875] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background Inflammation plays an important role in the progression of sporadic aortic dissection (AD). Immune cells, especially macrophages, infiltrate the aorta and secrete inflammatory cytokines and matrix metalloproteinases to cause degradation of the extracellular matrix, thereby contributing to the pathogenesis of AD. However, the cellular heterogeneity within these immune cells has not been fully characterized. Methods We used single-cell RNA sequencing to profile the transcriptomes of all immune cells in AD tissue and normal aorta. Using magnetic-activated cell sorting gating on CD45, we obtained a higher resolution identification of the immune cell subsets in the aorta. Results We observed significant differences in the proportion of major immune cell subpopulations between AD and normal aorta tissues. Macrophages accounted for a higher percentage in the normal aorta, while the proportions of T cells, B cells and natural killer (NK) cells were all increased in AD tissues. Macrophage clusters that expanded in AD tissues originated primarily from circulating monocytes and expressed genes encoding proinflammatory cytokines and molecules involved in tissue repair. T and NK cells in AD tissues exhibited enhanced cytotoxic properties. A cluster of CD4+ T cells that had expanded in AD tissues was Th17-like and might contribute to the pathogenesis of AD. Cell–cell interaction analysis highlighted the increased communication between macrophages and T cells, which primarily regulated the costimulation of T cells. Conclusions Our study provides a comprehensive characterization of immune cells in the dissected aorta with an emphasis on the role of macrophages and T cells. The information from our study improves our understanding of immune mechanisms in AD formation and helps to identify additional useful targets for early diagnosis or therapy of AD.
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Affiliation(s)
- Yifan Liu
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Lingwei Zou
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Hanfei Tang
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Jie Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hao Liu
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Xiaolang Jiang
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Baohong Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- *Correspondence: Weiguo Fu
| | - Zhihui Dong
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
- Zhihui Dong
| | - Weiguo Fu
- Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
- Baohong Jiang
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Zhai Z, Zhang X, Ding Y, Huang Z, Li Q, Zheng M, Cho K, Dong Z, Fu W, Chen Z, Jiang B. Eugenol restrains abdominal aortic aneurysm progression with down‐regulations on
NF‐κB
and
COX
‐2. Phytother Res 2022; 36:928-937. [PMID: 35132703 DOI: 10.1002/ptr.7358] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/14/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Ziyi Zhai
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- College of Pharmacy, China Medical University, Liaoning, China
| | - Xianjing Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yuchao Ding
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- College of Pharmacy, China Medical University, Liaoning, China
| | - Ziming Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Qian Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- College of Pharmacy, China Medical University, Liaoning, China
| | - Mingyue Zheng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Kenka Cho
- Department of Acupuncture, Takarazuka University of Medical and Health Care, Takarazuka-city, Japan
| | - Zhihui Dong
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiguo Fu
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zaixing Chen
- College of Pharmacy, China Medical University, Liaoning, China
| | - Baohong Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Siennicka A, Adamowicz M, Grzesch N, Kłysz M, Woźniak J, Cnotliwy M, Galant K, Jastrzębska M. Association of Aneurysm Tissue Neutrophil Mediator Levels with Intraluminal Thrombus Thickness in Patients with Abdominal Aortic Aneurysm. Biomolecules 2022; 12:biom12020254. [PMID: 35204755 PMCID: PMC8961541 DOI: 10.3390/biom12020254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/26/2022] [Accepted: 02/02/2022] [Indexed: 12/04/2022] Open
Abstract
An intraluminal thrombus (ILT), which accumulates large numbers of neutrophils, plays a key role in abdominal aortic aneurysm (AAA) pathogenesis. This study aimed to compare levels of selected neutrophil inflammatory mediators in thick and thin ILT, plus adjacent AAA walls, to determine whether levels depend on ILT thickness. Neutrophil mediator levels were analysed by enzyme-linked immunosorbent assays in thick and thin segments of ILT, plus adjacent aneurysm wall sections, taken from one aneurysm sac each from 36 AAA patients. In aneurysmal walls covered by thick ILT, neutrophil elastase and TNF-a levels were significantly higher, as were concentrations of IL-6, in thick ILT compared to thin layers. Positive correlations of NGAL, MPO, and neutrophil elastase were observed between thick ILT and the adjacent wall and thin ILT and the adjacent wall, suggesting that these mediators probably infiltrate thick AAA compartments as well as thin. These observations might support the idea that neutrophil mediators and inflammatory cytokines differentially accumulate in AAA tissues according to ILT thickness. The increased levels of neutrophil mediators within thicker AAA segments might suggest the existence of an intensified proinflammatory state that in turn presumably might preferentially weaken the AAA wall at that region.
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Affiliation(s)
- Aldona Siennicka
- Department of Laboratory Diagnostics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.S.); (M.A.); (N.G.); (M.J.)
| | - Monika Adamowicz
- Department of Laboratory Diagnostics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.S.); (M.A.); (N.G.); (M.J.)
| | - Natalie Grzesch
- Department of Laboratory Diagnostics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.S.); (M.A.); (N.G.); (M.J.)
| | - Magdalena Kłysz
- Department of Laboratory Diagnostics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.S.); (M.A.); (N.G.); (M.J.)
- Correspondence: ; Tel.: +48-914661505
| | - Jarosław Woźniak
- Institute of Mathematics, University of Szczecin, Wielkopolska 15, 70-451 Szczecin, Poland;
| | - Miłosław Cnotliwy
- Department of Vascular Surgery and Angiology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Katarzyna Galant
- Department of Laboratory Medicine, Chair of Microbiology, Immunological Diagnostics and Laboratory Medicine, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Maria Jastrzębska
- Department of Laboratory Diagnostics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.S.); (M.A.); (N.G.); (M.J.)
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Lopez-Navarro ER, Gutierrez J. Metalloproteinases and their inhibitors in neurological disease. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 395:27-38. [PMID: 34851449 DOI: 10.1007/s00210-021-02188-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/19/2021] [Indexed: 11/29/2022]
Abstract
Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological processes. We aim to review the MMP inhibition from a clinical perspective and its possible therapeutic use in the future. MMPs play a role in various neurodegenerative and cerebrovascular diseases such as large artery atherosclerosis and ischemic stroke; for example, MMPs increase blood-brain barrier permeability favoring neuroinflammation. Synthetic MMPs inhibitors have been tested mostly in oncological trials and failed to demonstrate efficacy; some of them were discontinued because of the severe adverse reactions. Tetracyclines, in submicrobial doses, act as an MMP inhibitor, although tetracyclines have not yet been proven effective in several neurological conditions in which they were tested against placebo; it is uncertain whether there may be a use for tetracyclines in cerebrovascular disease, as a neuroprotective agent or in dolichoectasia.
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Affiliation(s)
| | - Jose Gutierrez
- Department of Neurology, Columbia University Irving Medical Center, 710 W 168th Street, 6th floor, Suite 639, New York, NY, 10032, USA.
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Martínez-González J, Cañes L, Alonso J, Ballester-Servera C, Rodríguez-Sinovas A, Corrales I, Rodríguez C. NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond. Int J Mol Sci 2021; 22:ijms222111371. [PMID: 34768801 PMCID: PMC8583700 DOI: 10.3390/ijms222111371] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors. Nuclear receptors of the subfamily 4 group A (NR4A) have recently emerged as key master genes in multiple cellular processes and vital functions of different organs, and have been involved in a variety of high-incidence human pathologies including atherosclerosis and other CVDs. This paper reviews the major findings involving NR4A3 (Neuron-derived Orphan Receptor 1, NOR-1) in the cardiovascular remodeling operating in these diseases.
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Affiliation(s)
- José Martínez-González
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain; (L.C.); (J.A.); (C.B.-S.)
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, Spain
- Correspondence: (J.M.-G.); (C.R.); Tel.: +34-93-5565896 (J.M.-G.); +34-93-5565897 (C.R.)
| | - Laia Cañes
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain; (L.C.); (J.A.); (C.B.-S.)
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, Spain
| | - Judith Alonso
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain; (L.C.); (J.A.); (C.B.-S.)
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, Spain
| | - Carme Ballester-Servera
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain; (L.C.); (J.A.); (C.B.-S.)
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, Spain
| | - Antonio Rodríguez-Sinovas
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Irene Corrales
- Laboratorio de Coagulopatías Congénitas, Banc de Sang i Teixits (BST), 08005 Barcelona, Spain;
- Medicina Transfusional, Vall d’Hebron Institut de Recerca-Universitat Autònoma de Barcelona (VHIR-UAB), 08035 Barcelona, Spain
| | - Cristina Rodríguez
- CIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain;
- Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, Spain
- Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), 08041 Barcelona, Spain
- Correspondence: (J.M.-G.); (C.R.); Tel.: +34-93-5565896 (J.M.-G.); +34-93-5565897 (C.R.)
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Kim SH, Ko IG, Jin JJ, Hwang L, Baek SS. Treadmill exercise ameliorates impairment of spatial learning memory in pups born to old and obese mother rats. J Exerc Rehabil 2021; 17:234-240. [PMID: 34527634 PMCID: PMC8413911 DOI: 10.12965/jer.2142466.233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/01/2021] [Indexed: 12/03/2022] Open
Abstract
Memory state of rat pups born to old and obese mother rats and the effect of a treadmill running of mother rats on the memory of rat pups were studied. The radial 8-arm maze test was performed to detect spatial learning memory, and the level of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in the hippocampus was measured by enzyme-linked immunoassay. Western blotting was performed for the expression of nuclear factor kappa-light-chain-enhancer (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), matrix metalloproteinase (MMP)-9, and immunohistochemistry for caspase-3 was conducted. The newborn rats were classified into following groups: pups born to old mother rats, pups born to old mother rats with exercise, pups born to old and obese mother rats, and pups born to old and obese mother rats with exercise. Exercise of mother ameliorated spatial learning memory impairment, inhibited proinflammatory cytokines production, NF-κB expression, and IκB-α phosphorylation of the pups born to old and obese mother rats. Maternal exercise suppressed Bax expression, the number of caspase-3, the level of MMP-9, and enhanced Bcl-2 expression of the pups born to old and obese mother rats. When the maternal exercise was performed, the impairment of spatial learning memory in pups was ameliorated. Therefore, it can be seen that exercise during pregnancy of older and obese mothers is an important factor in fetal health management.
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Affiliation(s)
- Sang-Hoon Kim
- Department of Sport & Health Sciences, College of Art & Culture, Sangmyung University, Seoul, Korea.,Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Il-Gyu Ko
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Jun-Jang Jin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Lakkyong Hwang
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Seung-Soo Baek
- Department of Sport & Health Sciences, College of Art & Culture, Sangmyung University, Seoul, Korea
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Deleeuw V, De Clercq A, De Backer J, Sips P. An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome. J Exp Pharmacol 2021; 13:755-779. [PMID: 34408505 PMCID: PMC8366784 DOI: 10.2147/jep.s265271] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 07/19/2021] [Indexed: 12/26/2022] Open
Abstract
Marfan syndrome (MFS) is a heritable connective tissue disorder caused by pathogenic variants in the gene coding for the extracellular matrix protein fibrillin-1. While the disease affects multiple organ systems, the most life-threatening manifestations are aortic aneurysms leading to dissection and rupture. Other cardiovascular complications, including mitral valve prolapse, primary cardiomyopathy, and arrhythmia, also occur more frequently in patients with MFS. The standard medical care relies on cardiovascular imaging at regular intervals, along with pharmacological treatment with β-adrenergic receptor blockers aimed at reducing the aortic growth rate. When aortic dilatation reaches a threshold associated with increased risk of dissection, prophylactic surgical aortic replacement is performed. Although current clinical management has significantly improved the life expectancy of patients with MFS, no cure is available and fatal complications still occur, underscoring the need for new treatment options. In recent years, preclinical studies have identified a number of potentially promising therapeutic targets. Nevertheless, the translation of these results into clinical practice has remained challenging. In this review, we present an overview of the currently available knowledge regarding the underlying pathophysiological processes associated with MFS cardiovascular pathology. We then summarize the treatment options that have been developed based on this knowledge and are currently in different stages of preclinical or clinical development, provide a critical review of the limitations of current studies and highlight potential opportunities for future research.
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Affiliation(s)
- Violette Deleeuw
- Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, 9000, Belgium
| | - Adelbert De Clercq
- Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, 9000, Belgium
| | - Julie De Backer
- Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, 9000, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, 9000, Belgium
| | - Patrick Sips
- Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, 9000, Belgium
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Mansour NO, Shama MA, Werida RH. The effect of doxycycline on neuron-specific enolase in patients with traumatic brain injury: a randomized controlled trial. Ther Adv Chronic Dis 2021; 12:20406223211024362. [PMID: 34262678 PMCID: PMC8246481 DOI: 10.1177/20406223211024362] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/13/2021] [Indexed: 11/24/2022] Open
Abstract
Objective: We aimed to examine the effect of doxycycline on serum levels of neuron-specific enolase (NSE), a marker of neuronal damage in traumatic brain injury (TBI) patients. Methods: Patients were randomly assigned into two groups (n = 25 each) to receive either placebo or doxycycline (200 mg daily), with their standard management for 7 days. Results: NSE serum levels in the doxycycline and control groups on day 3 were 14.66 ± 1.78 versus 18.09 ± 4.38 ng/mL, respectively (p = 0.008), and on day 7 were 12.3 ± 2.0 versus 16.43 ± 3.85 ng/mL, respectively (p = 0.003). Glasgow Coma Scale (GCS) on day 7 was 11.90 ± 2.83 versus 9.65 ± 3.44 in the doxycycline and control groups, respectively (p = 0.031). NSE serum levels and GCS scores were negatively correlated (r = −0.569, p < 0.001). Conclusion: Adjunctive early use of doxycycline might be a novel option that halts the ongoing secondary brain injury in patients with moderate to severe TBI. Future larger clinical trials are warranted to confirm these findings.
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Affiliation(s)
- Noha O Mansour
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, El-Dakahelia, Egypt
| | - Mohamed A Shama
- Emergency Medicine and Traumatology Department, Faculty of Medicine, Tanta University, Tanta, El-Gharbia, Egypt
| | - Rehab H Werida
- Clinical Pharmacy and Pharmacy Practice Department - Faculty of Pharmacy, Damanhour University, Elchorniash Street, Damanhour, Elbehairah 31527, Egypt
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39
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Current pharmacological management of aortic aneurysm. J Cardiovasc Pharmacol 2021; 78:211-220. [PMID: 33990514 DOI: 10.1097/fjc.0000000000001054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/23/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Aortic aneurysm (AA) remains one of the primary causes of death worldwide. Of the major treatments, prophylactic operative repair is used for AA to avoid potential aortic dissection (AD) or rupture. To halt the development of AA and alleviate its progression into AD, pharmacological treatment has been investigated for years. Currently, β-adrenergic blocking agents, losartan, irbesartan, angiotensin-converting-enzyme inhibitors, statins, antiplatelet agents, doxycycline, and metformin have been investigated as potential candidates for preventing AA progression. However, the paradox between preclinical successes and clinical failures still exists, with no medical therapy currently available for ideally negating the disease progression. This review describes the current drugs used for pharmacological management of AA and their individual potential mechanisms. Preclinical models for drug screening and evaluation are also discussed to gain a better understanding of the underlying pathophysiology and ultimately find new therapeutic targets for AA.
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40
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Chaves Filho AJM, Mottin M, Soares MVR, Jucá PM, Andrade CH, Macedo DS. Tetracyclines, a promise for neuropsychiatric disorders: from adjunctive therapy to the discovery of new targets for rational drug design in psychiatry. Behav Pharmacol 2021; 32:123-141. [PMID: 33595954 DOI: 10.1097/fbp.0000000000000585] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, represent the leading cause of disability worldwide. Nevertheless, the current pharmacotherapy has several limitations, and a large portion of patients do not respond appropriately to it or remain with disabling symptoms overtime. Traditionally, pharmacological interventions for psychiatric disorders modulate dysfunctional neurotransmitter systems. In the last decades, compelling evidence has advocated for chronic inflammatory mechanisms underlying these disorders. Therefore, the repurposing of anti-inflammatory agents has emerged as an attractive therapeutic tool for mental disorders. Minocycline (MINO) and doxycycline (DOXY) are semisynthetic second-generation tetracyclines with neuroprotective and anti-inflammatory properties. More recently, the most promising results obtained in clinical trials using tetracyclines for major psychiatric disorders were for schizophrenia. In a reverse translational approach, tetracyclines inhibit microglial reactivity and toxic inflammation by mechanisms related to the inhibition of nuclear factor kappa B signaling, cyclooxygenase 2, and matrix metalloproteinases. However, the molecular mechanism underlying the effects of these tetracyclines is not fully understood. Therefore, the present review sought to summarize the latest findings of MINO and DOXY use for major psychiatric disorders and present the possible targets to their molecular and behavioral effects. In conclusion, tetracyclines hold great promise as (ready-to-use) agents for being used as adjunctive therapy for human neuropsychiatric disorders. Hence, the understanding of their molecular mechanisms may contribute to the discovery of new targets for the rational drug design of novel psychoactive agents.
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Affiliation(s)
- Adriano José Maia Chaves Filho
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Melina Mottin
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Michele Verde-Ramo Soares
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
| | - Paloma Marinho Jucá
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
| | - Carolina Horta Andrade
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Danielle S Macedo
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
- National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, SP, Brazil
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Hadzic S, Wu CY, Gredic M, Kojonazarov B, Pak O, Kraut S, Sommer N, Kosanovic D, Grimminger F, Schermuly RT, Seeger W, Bellusci S, Weissmann N. The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2021; 320:L903-L915. [PMID: 33760647 DOI: 10.1152/ajplung.00048.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.
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Affiliation(s)
- Stefan Hadzic
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Cheng-Yu Wu
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Marija Gredic
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Baktybek Kojonazarov
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.,Institute for Lung Health (ILH), Justus-Liebig-University, Giessen, Germany
| | - Oleg Pak
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Simone Kraut
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Natascha Sommer
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Djuro Kosanovic
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.,Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Friedrich Grimminger
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Ralph T Schermuly
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Werner Seeger
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.,Institute for Lung Health (ILH), Justus-Liebig-University, Giessen, Germany.,Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Saverio Bellusci
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
| | - Norbert Weissmann
- Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany
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Ferrari D, la Sala A, Milani D, Celeghini C, Casciano F. Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development. Front Immunol 2021; 11:617804. [PMID: 33664731 PMCID: PMC7921745 DOI: 10.3389/fimmu.2020.617804] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a hardening and narrowing of arteries causing a reduction of blood flow. It is a leading cause of death in industrialized countries as it causes heart attacks, strokes, and peripheral vascular disease. Pathogenesis of the atherosclerotic lesion (atheroma) relies on the accumulation of cholesterol-containing low-density lipoproteins (LDL) and on changes of artery endothelium that becomes adhesive for monocytes and lymphocytes. Immunomediated inflammatory response stimulated by lipoprotein oxidation, cytokine secretion and release of pro-inflammatory mediators, worsens the pathological context by amplifying tissue damage to the arterial lining and increasing flow-limiting stenosis. Formation of thrombi upon rupture of the endothelium and the fibrous cup may also occur, triggering thrombosis often threatening the patient’s life. Purinergic signaling, i.e., cell responses induced by stimulation of P2 and P1 membrane receptors for the extracellular nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine), has been implicated in modulating the immunological response in atherosclerotic cardiovascular disease. In this review we will describe advancements in the understanding of purinergic modulation of the two main immune cells involved in atherogenesis, i.e., monocytes/macrophages and T lymphocytes, highlighting modulation of pro- and anti-atherosclerotic mediated responses of purinergic signaling in these cells and providing new insights to point out their potential clinical significance.
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Affiliation(s)
- Davide Ferrari
- Department of Life Science and Biotechnology, Section of Microbiology and Applied Pathology, University of Ferrara, Ferrara, Italy
| | - Andrea la Sala
- Certification Unit, Health Directorate, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
| | - Daniela Milani
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Claudio Celeghini
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Fabio Casciano
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
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Dalhoff A. Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks? Infection 2021; 49:29-56. [PMID: 33367978 PMCID: PMC7851017 DOI: 10.1007/s15010-020-01536-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
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Affiliation(s)
- Axel Dalhoff
- Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
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Cañes L, Martí-Pàmies I, Ballester-Servera C, Alonso J, Serrano E, Briones AM, Rodríguez C, Martínez-González J. High NOR-1 (Neuron-Derived Orphan Receptor 1) Expression Strengthens the Vascular Wall Response to Angiotensin II Leading to Aneurysm Formation in Mice. Hypertension 2020; 77:557-570. [PMID: 33356402 DOI: 10.1161/hypertensionaha.120.16078] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
No drug therapy has shown to limit abdominal aortic aneurysm (AAA) growth or rupture, and the understanding of the disease biology is incomplete; whereby, one challenge of vascular medicine is the development of good animal models and therapies for this life-threatening condition. The nuclear receptor NOR-1 (neuron-derived orphan receptor 1) controls biological processes involved in AAA; however, whether it plays a role in this pathology is unknown. Through a gain-of-function approach we assessed the impact of NOR-1 expression on the vascular response to Ang II (angiotensin II). We used 2 mouse models that overexpress human NOR-1 in the vasculature, one of them specifically in vascular smooth muscle cells. NOR-1 transgenesis amplifies the response to Ang II enhancing vascular inflammation (production of proinflammatory cytokines, chemokines, and reactive oxygen species), increasing MMP (matrix metalloproteinase) activity and disturbing elastin integrity, thereby broking the resistance of C57BL/6 mice to Ang II-induced AAA. Genes encoding for proteins critically involved in AAA formation (Il [interleukin]-6, Il-1β, Cxcl2, [C-X-C motif chemokine ligand 2], Mcp-1 [monocyte chemoattractant protein 1], and Mmp2) were upregulated in aneurysmal tissues. Both animal models show a similar incidence and severity of AAA, suggesting that high expression of NOR-1 in vascular smooth muscle cell is a sufficient condition to strengthen the response to Ang II. These alterations, including AAA formation, were prevented by the MMP inhibitor doxycycline. Microarray analysis identified gene sets that could explain the susceptibility of transgenic animals to Ang II-induced aneurysms, including those related with extracellular matrix remodeling, inflammatory/immune response, sympathetic activity, and vascular smooth muscle cell differentiation. These results involve NOR-1 in AAA and validate mice overexpressing this receptor as useful experimental models.
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Affiliation(s)
- Laia Cañes
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.)
| | - Ingrid Martí-Pàmies
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.)
| | - Carme Ballester-Servera
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.)
| | - Judith Alonso
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.)
| | - Elena Serrano
- Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.).,Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, Spain (E.S., C.R.)
| | - Ana M Briones
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz, Spain (A.M.B.)
| | - Cristina Rodríguez
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.).,Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, Spain (E.S., C.R.)
| | - José Martínez-González
- From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).,CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).,Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain (L.C., I.M.-P., C.B.-S., J.A., E.S., C.R., J.M.-G.)
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Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Taruya A, Furuta M, Mukaida N, Kondo T. Prevention of CaCl 2-induced aortic inflammation and subsequent aneurysm formation by the CCL3-CCR5 axis. Nat Commun 2020; 11:5994. [PMID: 33239616 PMCID: PMC7688638 DOI: 10.1038/s41467-020-19763-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 10/29/2020] [Indexed: 11/27/2022] Open
Abstract
Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3-/- mice and Ccr5-/- but not Ccr1-/- mice exhibit exaggerated CaCl2-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl2-treated Ccl3-/- mice. On the contrary, CCL3 treatment attenuates CaCl2-induced AAA in both wild-type and Ccl3-/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl2-induced AAA by suppressing MMP-9 expression.
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MESH Headings
- Angiotensin II/toxicity
- Animals
- Anti-Inflammatory Agents/metabolism
- Aorta, Abdominal/drug effects
- Aorta, Abdominal/immunology
- Aorta, Abdominal/pathology
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/immunology
- Aortic Aneurysm, Abdominal/pathology
- Calcium Chloride/toxicity
- Chemokine CCL3/genetics
- Chemokine CCL3/metabolism
- Disease Models, Animal
- Humans
- Inflammation Mediators/metabolism
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Matrix Metalloproteinase 9/metabolism
- Mice
- Mice, Knockout
- Receptors, CCR1/genetics
- Receptors, CCR1/metabolism
- Receptors, CCR5/genetics
- Receptors, CCR5/metabolism
- Signal Transduction/genetics
- Signal Transduction/immunology
- Specific Pathogen-Free Organisms
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yumi Kuninaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mizuho Nosaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akihiko Kimura
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Taruya
- Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan
| | - Machi Furuta
- Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
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46
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Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases. Antioxidants (Basel) 2020; 9:antiox9111150. [PMID: 33228202 PMCID: PMC7699558 DOI: 10.3390/antiox9111150] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA) are serious arterial diseases in the aorta and brain, respectively. AAA and IA are associated with old age in males and females, respectively, and if rupture occurs, they carry high morbidity and mortality. Aneurysmal subarachnoid hemorrhage (SAH) due to IA rupture has a high rate of complication and fatality. Despite these severe clinical outcomes, preventing or treating these devastating diseases remains an unmet medical need. Inflammation and oxidative stress are shared pathologies of these vascular diseases. Therefore, therapeutic strategies have focused on reducing inflammation and reactive oxygen species levels. Interestingly, in response to cellular stress, the inducible heme oxygenase-1 (HO-1) is highly upregulated and protects against tissue injury. HO-1 degrades the prooxidant heme and generates molecules with antioxidative and anti-inflammatory properties, resulting in decreased oxidative stress and inflammation. Therefore, increasing HO-1 activity is an attractive option for therapy. Several HO-1 inducers have been identified and tested in animal models for preventing or alleviating AAA, IA, and SAH. However, clinical trials have shown conflicting results. Further research and the development of highly selective HO-1 regulators may be needed to prevent the initiation and progression of AAA, IA, or SAH.
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47
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Golledge J, Krishna SM, Wang Y. Mouse models for abdominal aortic aneurysm. Br J Pharmacol 2020; 179:792-810. [PMID: 32914434 DOI: 10.1111/bph.15260] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/25/2020] [Accepted: 09/03/2020] [Indexed: 12/21/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Smriti Murali Krishna
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Yutang Wang
- Discipline of Life Sciences, School of Health and Life Sciences, Federation University Australia, Ballarat, Victoria, Australia
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48
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Golledge J, Moxon JV, Singh TP, Bown MJ, Mani K, Wanhainen A. Lack of an effective drug therapy for abdominal aortic aneurysm. J Intern Med 2020; 288:6-22. [PMID: 31278799 DOI: 10.1111/joim.12958] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, P = 0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregation inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.
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Affiliation(s)
- J Golledge
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Qld, Australia.,Centre for Molecular Therapeutics, The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Qld, Australia
| | - J V Moxon
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,Centre for Molecular Therapeutics, The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Qld, Australia
| | - T P Singh
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Qld, Australia
| | - M J Bown
- Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK
| | - K Mani
- Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - A Wanhainen
- Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
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49
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Hosseini V, Mallone A, Mirkhani N, Noir J, Salek M, Pasqualini FS, Schuerle S, Khademhosseini A, Hoerstrup SP, Vogel V. A Pulsatile Flow System to Engineer Aneurysm and Atherosclerosis Mimetic Extracellular Matrix. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2000173. [PMID: 32596117 PMCID: PMC7312268 DOI: 10.1002/advs.202000173] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Indexed: 06/11/2023]
Abstract
Alterations of blood flow patterns strongly correlate with arterial wall diseases such as atherosclerosis and aneurysm. Here, a simple, pumpless, close-loop, easy-to-replicate, and miniaturized flow device is introduced to concurrently expose 3D engineered vascular smooth muscle tissues to high-velocity pulsatile flow versus low-velocity disturbed flow conditions. Two flow regimes are distinguished, one that promotes elastin and impairs collagen I assembly, while the other impairs elastin and promotes collagen assembly. This latter extracellular matrix (ECM) composition shares characteristics with aneurysmal or atherosclerotic tissue phenotypes, thus recapitulating crucial hallmarks of flow-induced tissue morphogenesis in vessel walls. It is shown that the mRNA levels of ECM of collagens and elastin are not affected by the differential flow conditions. Instead, the differential gene expression of matrix metalloproteinase (MMP) and their inhibitors (TIMPs) is flow-dependent, and thus drives the alterations in ECM composition. In further support, treatment with doxycycline, an MMP inhibitor and a clinically used drug to treat vascular diseases, halts the effect of low-velocity flow on the ECM remodeling. This illustrates how the platform can be exploited for drug efficacy studies by providing crucial mechanistic insights into how different therapeutic interventions may affect tissue growth and ECM assembly.
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Affiliation(s)
- Vahid Hosseini
- Laboratory of Applied MechanobiologyInstitute of Translational MedicineDepartment of Health Sciences and TechnologyETH ZurichZurich8093Switzerland
- Present address:
Department of BioengineeringUniversity of California‐Los AngelesLos AngelesCA90095USA
| | - Anna Mallone
- Institute for Regenerative Medicine (IREM)University of Zurich and Wyss Translational Center ZurichZurich8952Switzerland
| | - Nima Mirkhani
- Responsive Biomedical Systems LabInstitute of Translational MedicineDepartment of Health Sciences and TechnologyETH ZurichZurich8093Switzerland
| | - Jerome Noir
- Institute of GeophysicsDepartment of Earth SciencesETH ZurichZurich8092Switzerland
| | - Mehdi Salek
- Department of Mechanical EngineeringMassachusetts Institute of TechnologyBostonMA02139USA
| | - Francesco Silvio Pasqualini
- Institute for Regenerative Medicine (IREM)University of Zurich and Wyss Translational Center ZurichZurich8952Switzerland
- Synthetic Physiology LaboratoryDepartment of Civil Engineering and ArchitectureUniversity of PaviaPavia27100Italy
| | - Simone Schuerle
- Responsive Biomedical Systems LabInstitute of Translational MedicineDepartment of Health Sciences and TechnologyETH ZurichZurich8093Switzerland
| | - Ali Khademhosseini
- Department of BioengineeringUniversity of California‐Los AngelesLos AngelesCA90095USA
| | - Simon P. Hoerstrup
- Institute for Regenerative Medicine (IREM)University of Zurich and Wyss Translational Center ZurichZurich8952Switzerland
| | - Viola Vogel
- Laboratory of Applied MechanobiologyInstitute of Translational MedicineDepartment of Health Sciences and TechnologyETH ZurichZurich8093Switzerland
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50
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Doxycycline improves traumatic brain injury outcomes in a murine survival model. J Trauma Acute Care Surg 2020; 89:435-440. [DOI: 10.1097/ta.0000000000002801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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