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1
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Affiliation(s)
- Wen Wu
- Department of Cardiology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211112, P. R. China
| | - Dai-Min Zhang
- Department of Cardiology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211112, P. R. China
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2
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Cai Y, Zang GY, Huang Y, Sun Z, Zhang LL, Qian YJ, Yuan W, Wang ZQ. Advances in neovascularization after diabetic ischemia. World J Diabetes 2022; 13:926-939. [PMID: 36437864 PMCID: PMC9693741 DOI: 10.4239/wjd.v13.i11.926] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/09/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
With the high incidence of diabetes around the world, ischemic complications cause a serious influence on people's production and living. Neovascularization plays a significant role in its development. Therefore, neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years. Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation. When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia, they induce the secretion of cytokines, such as vascular endothelial growth factor and hypoxia-inducible factor, activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathways, trigger oxidative stress response, activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels, remodeling them into mature blood vessels and restoring blood supply. However, the hypoglycemic condition has different impacts on neovascularization. Consequently, this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia, increase our un-derstanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients' pain. It is believed that in the near future, neovascularization will bring more benefits and hope to patients with diabetes.
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Affiliation(s)
- Yue Cai
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Guang-Yao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yan Huang
- Department of Ophthalmology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Li-Li Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yong-Jiang Qian
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhong-Qun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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3
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Fang Y, Yang R, Hou Y, Wang Y, Yang N, Xu M, Li S, Gao S, Jiang M, Fan J, Hu Y, Xu Z, Gao L, Cao F. Dual-modality Imaging of Angiogenesis in Unstable Atherosclerotic Plaques with VEGFR2-Targeted Upconversion Nanoprobes in vivo. Mol Imaging Biol 2022; 24:721-731. [PMID: 35604528 PMCID: PMC9581814 DOI: 10.1007/s11307-022-01721-5] [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: 10/08/2021] [Revised: 02/18/2022] [Accepted: 03/14/2022] [Indexed: 10/18/2022]
Abstract
AIM Angiogenesis plays a major role in atherosclerotic plaque development and instability. Our study aims to develop a novel optical and magnetic resonance (MR) dual-modality molecular imaging probe to early detect unstable plaques in vivo by targeting biomarkers of angiogenesis in murine models of atherosclerosis (AS). METHODS Immunofluorescence and western blot were used to detect the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in activated Human Umbilical Vein Endothelial Cells (HUVECs). After synthesis and identification of novel short peptide VRBP1-targeted VEGFR2, HUVECs were co-cultured with FITC-VRBP1 to test specific affinity of VRBP1. Then VRBP1-UCNPstargeting VEGFR2 were constructed by conjugating VRBP1 to the surface of NaGdF4:Yb,Er@NaGdF4 nanoparticles. The characterization of the nanoparticles was performed by transmission electron microscopy (TEM), distribution of size, hydrodynamic size, zeta potential, absorption spectra, emission spectra, imaging intensity of different concentrations, binding affinity and cytotoxicity of nanoprobes in vitro. The upconversion luminescence (UCL) and MR imaging were performed to identify unstable atherosclerotic plaque in ApoE-/- mice in vivo and ex vivo. Morphological staining was used to verify AS model and angiogenesis, and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) was used to confirm accumulation of the nanoparticles after imaging. RESULTS After induced by hypoxia and ox-LDL, the expression of VEGFR2 in activated HUVECs was enhanced. FITC-VRBP1 can specifically bind to the HUVECs. Characterization of the nanoparticles showed that particles size is uniform with a stable structure, specific optical and MR signal, good binding affinity to VEGFR2 and low cytotoxicity. In vivo and ex vivo UCL imaging and quantitative analysis revealed that distinctive optical signal was observed in the regions of left carotid common arteries (LCCAs) of AS group after injection of VRBP1-UCNPs. Higher signal intensity on T1-weighted MR imaging appeared in the LCCA wall of AS group after injection. The results of morphological staining demonstrated angiogenesis in the atherosclerotic plaques, Gd ions in LCCAs, aortic arch and renal arteries bifurcations detected by ICP-AES confirmed accumulation of the nanoparticles in plaque. CONCLUSIONS We successfully design and synthesize a novel UCNPs using peptide VRBP1 targeting to VEGFR2. In vivo imaging demonstrates that VRBP1-UCNPs can be used to perform optical/MR dual-modality imaging targeting angiogenesis in plaques, which is a promising technique to early detect unstable atherosclerosis.
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Affiliation(s)
- Yan Fang
- Medical School of Chinese PLA, Medical Department of Cardiovascular Disease in Sixth Medical Center & National Research Center for Geriatric Diseases, Chinese PLA General Hospital Chinese PLA General Hospital, Beijing, 100853, China
| | - Ruichen Yang
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi No.4 People Hospital, Jiangsu, 21400, Wuxi, China
| | - Yi Hou
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Yabin Wang
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Ning Yang
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Mengqi Xu
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Sulei Li
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Shan Gao
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Min Jiang
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jingyang Fan
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yazhuo Hu
- Institute of Gerontology institute, Second Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhenzhen Xu
- National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Lei Gao
- Medical School of Chinese PLA, Medical Department of Cardiovascular Disease in Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Feng Cao
- Medical School of Chinese PLA, Department of Cardiology in Second Medical Center &, National Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
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4
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Affiliation(s)
- Rocco Vergallo
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Filippo Crea
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS
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5
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Ameri P, Tini G, Spallarossa P, Mercurio V, Tocchetti CG, Porto I. Cardiovascular safety of the tyrosine kinase inhibitor nintedanib. Br J Clin Pharmacol 2021; 87:3690-3698. [PMID: 33620103 DOI: 10.1111/bcp.14793] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/12/2021] [Accepted: 02/12/2021] [Indexed: 01/07/2023] Open
Abstract
The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.
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Affiliation(s)
- Pietro Ameri
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiology Network, Genoa, Italy.,Department of Internal Medicine, University of Genova, Genoa, Italy
| | - Giacomo Tini
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiology Network, Genoa, Italy.,Department of Internal Medicine, University of Genova, Genoa, Italy
| | - Paolo Spallarossa
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiology Network, Genoa, Italy
| | - Valentina Mercurio
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Carlo Gabriele Tocchetti
- Department of Translational Medical Sciences, Federico II University, Naples, Italy.,Interdepartmental Center of Clinical and Translational Sciences (CIRCET), Federico II University, Naples, Italy
| | - Italo Porto
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiology Network, Genoa, Italy.,Department of Internal Medicine, University of Genova, Genoa, Italy
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6
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Maréchal P, Tridetti J, Nguyen ML, Wéra O, Jiang Z, Gustin M, Donneau AF, Oury C, Lancellotti P. Neutrophil Phenotypes in Coronary Artery Disease. J Clin Med 2020; 9:jcm9051602. [PMID: 32466264 PMCID: PMC7290445 DOI: 10.3390/jcm9051602] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
Clinical evidence indicates that innate immune cells may contribute to acute coronary syndrome (ACS). Our prospective study aimed at investigating the association of neutrophil phenotypes with ACS. 108 patients were categorized into chronic stable coronary artery disease (n = 37), unstable angina (UA) (n = 19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n = 25), and ST-Elevation Myocardial Infarction (STEMI) (n = 27). At the time of inclusion, blood neutrophil subpopulations were analysed by flow cytometry. Differential blood cell count and plasma levels of neutrophilic soluble markers were recorded at admission and, for half of patients, at six-month follow-up. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio than stable and UA patients (p < 0.0001), which normalized at six-month post-MI. Atypical low-density neutrophils were detected in the blood of the four patient groups. STEMI patients were characterized by elevated percentages of band cells compared to the other patients (p = 0.019). Multivariable logistic regression analysis revealed that plasma levels of total myeloperoxidase was associated with STEMI compared to stable (OR: 1.434; 95% CI: 1.119–1.837; P < 0.0001), UA (1.47; 1.146–1.886; p = 0.002), and NSTEMI (1.213; 1.1–1.134; p = 0.0001) patients, while increased neutrophil side scatter (SSC) signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033–14.184; p = 0.045). Hence, changes in neutrophil phenotype are concomitant to ACS.
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Affiliation(s)
- Patrick Maréchal
- Department of Cardiology, University of Liège Hospital, 4000 Liège, Belgium; (P.M.); (J.T.); (M.-L.N.)
| | - Julien Tridetti
- Department of Cardiology, University of Liège Hospital, 4000 Liège, Belgium; (P.M.); (J.T.); (M.-L.N.)
| | - Mai-Linh Nguyen
- Department of Cardiology, University of Liège Hospital, 4000 Liège, Belgium; (P.M.); (J.T.); (M.-L.N.)
| | - Odile Wéra
- Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium; (O.W.); (Z.J.); (M.G.)
| | - Zheshen Jiang
- Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium; (O.W.); (Z.J.); (M.G.)
| | - Maxime Gustin
- Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium; (O.W.); (Z.J.); (M.G.)
| | - Anne-Françoise Donneau
- Biostatistics Unit, Department of Public Health, University of Liège, 4000 Liège, Belgium;
| | - Cécile Oury
- Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium; (O.W.); (Z.J.); (M.G.)
- Correspondence: (C.O.); (P.L.)
| | - Patrizio Lancellotti
- Department of Cardiology, University of Liège Hospital, 4000 Liège, Belgium; (P.M.); (J.T.); (M.-L.N.)
- Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium; (O.W.); (Z.J.); (M.G.)
- Gruppo Villa Maria Care and Research, Anthea Hospital, 70123 Bari, Italy
- Correspondence: (C.O.); (P.L.)
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Brezinski M, Willard F, Rupnick M. Inadequate Intimal Angiogenesis as a Source of Coronary Plaque Instability: Implications for Healing. Circulation 2019; 140:1857-1859. [PMID: 31790293 PMCID: PMC7017589 DOI: 10.1161/circulationaha.119.042192] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Mark Brezinski
- Brigham and Women's Hospital, Boston, MA (M.B.)
- Harvard Medical School, Boston, MA (M.B.)
- Massachusetts Institute of Technology, Cambridge (M.B.)
- University of New England, Biddeford, ME (M.B., F.W.)
| | - Frank Willard
- University of New England, Biddeford, ME (M.B., F.W.)
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Wang Y, Zhang Y, Wang Z, Zhang J, Qiao RR, Xu M, Yang N, Gao L, Qiao H, Gao M, Cao F. Optical/MRI dual-modality imaging of M1 macrophage polarization in atherosclerotic plaque with MARCO-targeted upconversion luminescence probe. Biomaterials 2019; 219:119378. [PMID: 31382209 DOI: 10.1016/j.biomaterials.2019.119378] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 07/15/2019] [Accepted: 07/24/2019] [Indexed: 02/09/2023]
Abstract
Pro-inflammatory M1 macrophage is identified as a prominent component initializing the progress of vulnerable atherosclerotic plaque. Here, we constructed anti-MARCO NaGdF4:Yb,Er@NaGdF4 upconversion nanoparticles (UCNPs) by conjugating polyclonal MARCO antibody to the surface of NaGdF4:Yb,Er@NaGdF4via condensation reaction. UCNPs displayed highly mono-dispersion with average sizes of 26.7 ± 0.8 nm and favorable biocompatibility. In vivo upconversion optical imaging revealed that distinctive fluorescence signal could be observed in the regions of carotid artery 10 min post-injection, reached peak value at 1 h and decreased back to baseline at 24 h post-injection. The carotid artery wall demonstrated high signal intensity on T1-weighted MR images after anti-MARCO UCNPs injection, as determined by 7.0T MRI. Immunofluorescence staining of tissue section of carotid artery revealed that MARCO was highly abundant in shoulder regions of plaque. Anti-MARCO UCNPs is a promising optical/MRI dual-modality imaging probe which can non-invasively reflect M1 phenotype macrophages behavior in vivo.
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Affiliation(s)
- Yabin Wang
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Department of Cardiology, Chinese Eastern Theatre Naval Hospital, Zhejiang, 316000, China
| | - Yan Zhang
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; TEDA International Cardiovascular Hospital, Tianjin, 300457, China
| | - Zhao Wang
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jibin Zhang
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Rui Rui Qiao
- Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing, 100190, China
| | - Mengqi Xu
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Ning Yang
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Lei Gao
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Hongyu Qiao
- Department of Pediatric, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Mingyuan Gao
- Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing, 100190, China.
| | - Feng Cao
- Department of Cardiology & National Clinical Research Center of Geriatric Disease, 2nd Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
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