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Huang M, Du J, Wang Y, Ma S, Hu T, Shang J, Yu Q, Zhu X, Zhang G, Cong B. Tissue kallikrein-related peptidase8 protects rat heart against acute ischemia reperfusion injury. Int J Biol Macromol 2019; 140:1126-1133. [PMID: 31449861 DOI: 10.1016/j.ijbiomac.2019.08.195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/22/2019] [Accepted: 08/22/2019] [Indexed: 01/06/2023]
Abstract
Tissue kallikrein-related peptidases (KLKs) play important roles in acute cardiac injury and cardiac remodeling. However, the exact cardiac actions of KLK8 have not been determined. Transgenic rat overexpressing KLK8 was established to examine the role of KLK8 in the heart. Cardiac injury was induced by ischemia/reperfusion (I/R) and examined by infarct size measurement and TUNEL staining. The molecular mechanisms were investigated in cultured neonatal rat cardiomyocytes (CMs). Western blot analysis was used to determine the protein levels. KLK8 protein level was significantly increased in the cardiac ischemic risk area. KLK8 overexpression mitigated I/R-induced cardiac injury, as evidenced by decreased infarct size and apoptosis in cardiac ischemic risk area in vivo. Via in vitro studies, it was found that KLK8 overexpression attenuated the Hypoxia/Reoxygenation (H/R) injury in CMs; both B2R and PAR2 antagonist significantly attenuated KLK8-induced protective actions under H/R injury. Moreover, KLK8 overexpressed CMs showed significant higher phosphorylation levels of Akt, ERK1/2 and PKA under H/R stimulation; B2R antagonist attenuated the phosphorylation levels of Akt and ERK1/2, while PAR2 antagonist attenuated the phosphorylation levels of PKA and ERK1/2. KLK8 protects the heart against I/R-induced cardiac injury, which may represent a new therapeutic target in cardiac medicine.
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Affiliation(s)
- Meineng Huang
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Jiankui Du
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Yifei Wang
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Shiyu Ma
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Ting Hu
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Jing Shang
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Qing Yu
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Xiaoyan Zhu
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Guanxin Zhang
- Department of Cardiothoracic Surgery, Changhai Hospital, Shanghai 200433, China.
| | - Binhai Cong
- Department of Physiology, Second Military Medical University, Shanghai 200433, China.
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Micheu MM, Scarlatescu AI, Scafa-Udriste A, Dorobantu M. The Winding Road of Cardiac Regeneration-Stem Cell Omics in the Spotlight. Cells 2018; 7:255. [PMID: 30544622 PMCID: PMC6315576 DOI: 10.3390/cells7120255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 12/18/2022] Open
Abstract
Despite significant progress in treating ischemic cardiac disease and succeeding heart failure, there is still an unmet need to develop effective therapeutic strategies given the persistent high-mortality rate. Advances in stem cell biology hold great promise for regenerative medicine, particularly for cardiac regeneration. Various cell types have been used both in preclinical and clinical studies to repair the injured heart, either directly or indirectly. Transplanted cells may act in an autocrine and/or paracrine manner to improve the myocyte survival and migration of remote and/or resident stem cells to the site of injury. Still, the molecular mechanisms regulating cardiac protection and repair are poorly understood. Stem cell fate is directed by multifaceted interactions between genetic, epigenetic, transcriptional, and post-transcriptional mechanisms. Decoding stem cells' "panomic" data would provide a comprehensive picture of the underlying mechanisms, resulting in patient-tailored therapy. This review offers a critical analysis of omics data in relation to stem cell survival and differentiation. Additionally, the emerging role of stem cell-derived exosomes as "cell-free" therapy is debated. Last but not least, we discuss the challenges to retrieve and analyze the huge amount of publicly available omics data.
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Affiliation(s)
- Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
| | - Alina Ioana Scarlatescu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
| | - Alexandru Scafa-Udriste
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
- Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.
| | - Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
- Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.
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Liang D, He X, Wang Z, Li C, Gao B, Wu J, Bai Y. Remote limb ischemic postconditioning promotes motor function recovery in a rat model of ischemic stroke via the up-regulation of endogenous tissue kallikrein. CNS Neurosci Ther 2018; 24:519-527. [PMID: 29399973 PMCID: PMC6489769 DOI: 10.1111/cns.12813] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 01/16/2023] Open
Abstract
AIMS Remote ischemic conditionings, such as pre- and per-conditioning, are known to provide cardioprotection in animal models of ischemia. However, little is known about the neuroprotection effect of postconditioning after cerebral ischemia. In this study, we aim to evaluate the motor function rescuing effect of remote limb ischemic postconditioning (RIPostC) in a rat model of acute cerebral stroke. METHODS Left middle cerebral artery occlusion (MCAO) was performed to generate the rat model of ischemic stroke, followed by daily RIPostC treatment for maximum 21 days. The motor function after RIPostC was assessed with foot fault test and balance beam test. Local infarct volume was measured through MRI scanning. Neuronal status was evaluated with Nissl's, HE, and MAP2 immunostaining. Lectin immunostaining was performed to evaluate the microvessel density and area. RESULTS Daily RIPostC for more than 21 days promoted motor function recovery and provided long-lasting neuroprotection after MCAO. Reduced infarct volume, rescued neuronal loss, and enhanced microvessel density and size in the injured areas were observed. In addition, the RIPostC effect was associated with the up-regulation of endogenous tissue kallikrein (TK) level in circulating blood and local ischemic brain regions. A TK receptor antagonist HOE-140 partially reversed RIPostC-induced improvements, indicating the specificity of endogenous TK mediating the neuroprotection effect of RIPostC. CONCLUSION Our study demonstrates RIPostC treatment as an effective rehabilitation therapy to provide motor function recovery and alleviate brain impairment in a rat model of acute cerebral ischemia. We also for the first time provide evidence showing that the up-regulation of endogenous TK from remote conditioning regions underlies the observed effects of RIPostC.
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Affiliation(s)
- Dan Liang
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Xi‐Biao He
- Shanghai University of Medicine & Health SciencesShanghaiChina
| | - Zheng Wang
- Department of NeurologyHuashan HospitalState Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
| | - Ce Li
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Bei‐Yao Gao
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Jun‐Fa Wu
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Yu‐Long Bai
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
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Devetzi M, Goulielmaki M, Khoury N, Spandidos DA, Sotiropoulou G, Christodoulou I, Zoumpourlis V. Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review). Int J Mol Med 2018; 41:1177-1186. [PMID: 29328364 PMCID: PMC5819898 DOI: 10.3892/ijmm.2018.3361] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/02/2018] [Indexed: 12/12/2022] Open
Abstract
The tissue kallikrein-kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti-inflammatory, anti-apoptotic, anti-fibrotic and anti-oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well-characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases. Genetic modification enhances their inherent properties. MSCs or EPCs are competent cellular vehicles for drug and/or gene delivery in the targeted treatment of diseases. KLK1 gene delivery using adenoviral vectors or KLK1 protein infusion into injured tissues of animal models has provided particularly encouraging results in attenuating or reversing myocardial, renal and cerebrovascular ischemic phenotype and tissue damage, thus paving the way for the administration of genetically modified MSCs or EPCs with the human tissue KLK1 gene. Engraftment of KLK1-modified MSCs and/or KLK1-modified EPCs resulted in advanced beneficial outcome regarding heart and kidney protection and recovery from ischemic insults. Collectively, findings from pre-clinical studies raise the possibility that tissue KLK1 may be a novel future therapeutic target in the treatment of a wide range of cardiovascular, cerebrovascular and renal disorders.
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Affiliation(s)
- Marina Devetzi
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Goulielmaki
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Nicolas Khoury
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | | | - Ioannis Christodoulou
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
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Zanichelli A, Maurer M, Aberer W, Caballero T, Longhurst HJ, Bouillet L, Fabien V, Andresen I. Long-term safety of icatibant treatment of patients with angioedema in real-world clinical practice. Allergy 2017; 72:994-998. [PMID: 27926986 PMCID: PMC5434903 DOI: 10.1111/all.13103] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2016] [Indexed: 11/25/2022]
Abstract
The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real‐world setting. We analyzed safety data from 3025 icatibant‐treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off‐label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on‐label vs off‐label icatibant users.
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Affiliation(s)
- A. Zanichelli
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan; ASST Fatebenefratelli Sacco; Milan Italy
| | - M. Maurer
- Department of Dermatology and Allergy; Charité-Universitätsmedizin Berlin; Berlin Germany
| | - W. Aberer
- Department of Dermatology and Venerology; Medical University of Graz; Graz Austria
| | - T. Caballero
- Department of Allergy; Hospital La Paz Institute for Health Research (IdiPaz); Biomedical Research Network on Rare Diseases (CIBERER, U754); Madrid Spain
| | | | - L. Bouillet
- National Reference Centre for Angioedema; Internal Medicine Department; Grenoble University Hospital; Grenoble France
| | - V. Fabien
- Shire; Zug Switzerland at time of data analysis; now with Vifor Pharma, Glattbrugg, Switzerland
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Fu C, Li B, Sun Y, Ma G, Yao Y. Bradykinin inhibits oxidative stress-induced senescence of endothelial progenitor cells through the B2R/AKT/RB and B2R/EGFR/RB signal pathways. Oncotarget 2016; 6:24675-89. [PMID: 26360782 PMCID: PMC4694787 DOI: 10.18632/oncotarget.5071] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 08/13/2015] [Indexed: 01/08/2023] Open
Abstract
Circulating endothelial progenitor cells (EPCs) have multiple protective effects that facilitate repair of damage to tissues and organs. However, while various stressors are known to impair EPC function, the mechanisms of oxidative stress-induced EPC senescence remains unknown. We demonstrated that B2 receptor (B2R) expression on circulating CD34+ cells was significantly reduced in patients with diabetes mellitus (DM) as compared to healthy controls. Furthermore, CD34+ cell B2R expression in patients with DM was inversely correlated with plasma myeloperoxidase concentrations. Bradykinin (BK) treatment decreased human EPC (hEPC) senescence and intracellular oxygen radical production, resulting in reduced retinoblastoma 1 (RB) RNA expression in H2O2-induced senescent hEPCs and a reversal of the B2R downregulation that is normally observed in senescent cells. Furthermore, BK treatment of H2O2-exposed cells leads to elevated phosphorylation of RB, AKT, and cyclin D1 compared with H2O2-treatment alone. Antagonists of B2R, PI3K, and EGFR signaling pathways and B2R siRNA blocked BK protective effects. In summary, this study demonstrates that BK significantly inhibits oxidative stress-induced hEPC senescence though B2R-mediated activation of PI3K and EGFR signaling pathways.
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Affiliation(s)
- Cong Fu
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China
| | - Bing Li
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China
| | - Yuning Sun
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China
| | - Genshan Ma
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China
| | - Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China
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Zanichelli A, Wu MA, Andreoli A, Mansi M, Cicardi M. The safety of treatments for angioedema with hereditary C1 inhibitor deficiency. Expert Opin Drug Saf 2015; 14:1725-36. [PMID: 26429506 DOI: 10.1517/14740338.2015.1094053] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Angioedema is a localized and self-limiting edema of the subcutaneous and submucosal tissue. Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is the best characterized form of hereditary angioedema. In C1-INH-HAE, the reduced plasma levels of C1-INH cause instability of the contact system with release of bradykinin, the key mediator of angioedema. C1-INH-HAE is characterized by recurrent skin swelling, abdominal pain, and potentially life-threatening upper airways obstruction. Knowledge of the molecular mechanisms leading from C1-INH deficiency to angioedema allowed the development of several therapies. AREAS COVERED The aim of this review article is to discuss the safety of currently available treatments of C1-INH-HAE. The authors give an insight on the mechanism of action and safety profile of drugs for treatment of acute attacks and for short- and long-term prophylaxis. Evidence from systematic reviews, clinical trials, retrospective studies, and case reports is summarized in this review. EXPERT OPINION C1-INH-HAE is a disabling, life-threatening condition that lasts life-long. Different therapeutic approaches with different drugs provide significant benefit to patients. Safety profiles of these therapies are critical for optimal therapeutic decision and need to be known by C1-INH-HAE treating physicians for appropriate risk/benefit evaluation.
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Affiliation(s)
- Andrea Zanichelli
- a University of Milan, Luigi Sacco Hospital, Department of Biomedical and Clinical Sciences "Luigi Sacco" , Milan, Italy +39 02 50 31 98 29 ; +39 02 50 31 98 28 ;
| | - Maddalena Alessandra Wu
- a University of Milan, Luigi Sacco Hospital, Department of Biomedical and Clinical Sciences "Luigi Sacco" , Milan, Italy +39 02 50 31 98 29 ; +39 02 50 31 98 28 ;
| | - Arnaldo Andreoli
- a University of Milan, Luigi Sacco Hospital, Department of Biomedical and Clinical Sciences "Luigi Sacco" , Milan, Italy +39 02 50 31 98 29 ; +39 02 50 31 98 28 ;
| | - Marta Mansi
- a University of Milan, Luigi Sacco Hospital, Department of Biomedical and Clinical Sciences "Luigi Sacco" , Milan, Italy +39 02 50 31 98 29 ; +39 02 50 31 98 28 ;
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Zhu P, Yu H, Huang S, Xiang H, Li F, Zheng W. Synergistic effect of a tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 co‑expression vector on the proliferation of rat vascular smooth muscle cells. Mol Med Rep 2015; 12:5671-8. [PMID: 26252163 PMCID: PMC4581792 DOI: 10.3892/mmr.2015.4198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Accepted: 06/22/2015] [Indexed: 12/05/2022] Open
Abstract
Tissue kallikrein 1 (TK1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) are important in inhibiting vascular smooth muscle cell (VSMC) proliferation and improving vascular remodeling, respectively. It was hypothesized that a combination of TK1 and TIMP1 genes, mediated by an adenovirus vector could augment or act in synergy to enhance the inhibitory effects. The promoter, mCMV carrying hTIMP1 cDNA was subcloned into pDC316-hTK1 to construct a recombinant plasmid carrying hTK1 and hTIMP1 genes. Subsequently, the double gene plasmid and adenovirus backbone plasmid were packaged into HEK293A cells. Gene transcription and protein expression were examined, respectively using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting assays. VSMC proliferation was assessed using cell counting and methyl-thiazolyl-tetrazoliuin methods. The constructed plasmid containing hTK1 and hTIMP1 genes was correctly identified by means of PCR, double digestion and sequencing analysis. The co-expression vector, Ad-hTK1-hTIMP1 was successfully constructed and packaged into HEK293A cells. When VSMCs were transfected with the co-expression vector, the mRNA transcription and protein expression of hTK1 and hTIMP1 exhibited abundant expression in a concentration-dependent and time-dependent manner, independently. In conclusion, the co-expression vector synergistically inhibited the cell growth and proliferation induced by platelet-derived growth factor-BB compared with the single gene vector.
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Affiliation(s)
- Pengli Zhu
- Department of Geriatrics, Fujian Provincial Hospital Key Laboratory of Geriatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Huizhen Yu
- Department of Geriatrics, Fujian Provincial Hospital Key Laboratory of Geriatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Shujie Huang
- Department of Cardiology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Hong Xiang
- Department of Geriatrics, Fujian Provincial Hospital Key Laboratory of Geriatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Feng Li
- Department of Geriatrics, Fujian Provincial Hospital Key Laboratory of Geriatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Weiping Zheng
- Department of Geriatrics, Fujian Provincial Hospital Key Laboratory of Geriatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells. Stem Cells Int 2015; 2015:496512. [PMID: 26074973 PMCID: PMC4436457 DOI: 10.1155/2015/496512] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 02/23/2015] [Accepted: 02/24/2015] [Indexed: 01/17/2023] Open
Abstract
Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons ((1)H) and high charge and energy (HZE) nuclei (e.g., iron-(56)Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experiments in vitro we studied nontargeted effects induced by (1)H- and (56)Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24 h. A 2-15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24 h. Ex vivo analysis of BM-EPCs from single, low-dose, full-body (1)H- and (56)Fe-IR mice demonstrated a cyclical (early 5-24 h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.
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Regoli D, Gobeil F. Critical insights into the beneficial and protective actions of the kallikrein-kinin system. Vascul Pharmacol 2015; 64:1-10. [PMID: 25579779 DOI: 10.1016/j.vph.2014.12.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 12/26/2014] [Indexed: 12/20/2022]
Abstract
Hypertension is characterized by an imbalance between the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II AT-1 receptor antagonists (also known as sartans or ARBs) are potent modulators of these systems and are highly effective as first-line treatments for hypertension, diabetic nephropathies, and diseases of the brain and coronary arteries. However, these agents are mechanistically distinct and should not be considered interchangeable. In this mini-review, we provide novel insights into the often neglected roles of the KKS in the beneficial, protective, and reparative actions of ACEIs. Indeed, ACEIs are the only antihypertensive drugs that properly reduce the imbalance between the RAS and the KKS, thereby restoring optimal cardiovascular homeostasis and significantly reducing morbidity and the risk of all-cause mortality among individuals affected by hypertension and other cardiovascular diseases.
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Affiliation(s)
- Domenico Regoli
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
| | - Fernand Gobeil
- Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
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11
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Benton G, Arnaoutova I, George J, Kleinman HK, Koblinski J. Matrigel: from discovery and ECM mimicry to assays and models for cancer research. Adv Drug Deliv Rev 2014; 79-80:3-18. [PMID: 24997339 DOI: 10.1016/j.addr.2014.06.005] [Citation(s) in RCA: 308] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 06/19/2014] [Accepted: 06/24/2014] [Indexed: 01/06/2023]
Abstract
The basement membrane is an important extracellular matrix that is found in all epithelial and endothelial tissues. It maintains tissue integrity, serves as a barrier to cells and to molecules, separates different tissue types, transduces mechanical signals, and has many biological functions that help to maintain tissue specificity. A well-defined soluble basement membrane extract, termed BME/Matrigel, prepared from an epithelial tumor is similar in content to authentic basement membrane, and forms a hydrogel at 24-37°C. It is used in vitro as a substrate for 3D cell culture, in suspension for spheroid culture, and for various assays, such as angiogenesis, invasion, and dormancy. In vivo, BME/Matrigel is used for angiogenesis assays and to promote xenograft and patient-derived biopsy take and growth. Studies have shown that both the stiffness of the BME/Matrigel and its components (i.e. chemical signals) are responsible for its activity with so many different cell types. BME/Matrigel has widespread use in assays and in models that improve our understanding of tumor biology and help define therapeutic approaches.
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Qin T, Sun YY, Bai WW, Wang B, Xing YF, Liu Y, Yang RX, Zhao YX, Li JM. Period2 deficiency blunts hypoxia-induced mobilization and function of endothelial progenitor cells. PLoS One 2014; 9:e108806. [PMID: 25268972 PMCID: PMC4182576 DOI: 10.1371/journal.pone.0108806] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/25/2014] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND In the clinic, variations in circadian rhythm are evident in patients with cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. In this study, we focused on the role of the circadian gene period2 (per2) in mobilization and function of endothelial progenitor cells (EPCs) in vitro and in vivo after myocardial infarction (MI) in mice. METHODS AND RESULTS MI was produced by surgical ligation of the left anterior descending coronary artery in mice with and without per2 deficiency. Trans-thoracic echocardiography was used to evaluate cardiac function in mice. Per2-/- mice with MI showed decreased cardiac function and increased infarct size. The number of CD34+ cells and capillary density were decreased in the myocardium of per2-/- mice on immunohistochemistry. Flow cytometry revealed decreased number of circulating EPCs in per2-/- mice after MI. In vitro, per2-/- EPCs showed decreased migration and tube formation capacity under hypoxia. Western blot analysis revealed inhibited activation of extracellular signal-regulated kinase and Akt signaling in the bone marrow of per2-/- mice and inhibited PI3K/Akt expression in per2-/- EPCs under hypoxia. CONCLUSIONS Per2 modulates EPC mobilization and function after MI, which is important to recovery after MI in mice.
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Affiliation(s)
- Tao Qin
- Department of Emergency Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yuan-Yuan Sun
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan, Shandong, China
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Wen-Wu Bai
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Bo Wang
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yi-Fan Xing
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Liu
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan, Shandong, China
| | - Rui-Xue Yang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan, Shandong, China
| | - Yu-Xia Zhao
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
- * E-mail: (YXZ); (JML)
| | - Jian-Min Li
- Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong, China
- * E-mail: (YXZ); (JML)
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Chao J, Bledsoe G, Chao L. Kallikrein-kinin in stem cell therapy. World J Stem Cells 2014; 6:448-457. [PMID: 25258666 PMCID: PMC4172673 DOI: 10.4252/wjsc.v6.i4.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
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Gao L, Li P, Zhang J, Hagiwara M, Shen B, Bledsoe G, Chang E, Chao L, Chao J. Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 2014; 3:e001194. [PMID: 25237049 PMCID: PMC4323828 DOI: 10.1161/jaha.114.001194] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Kallistatin exerts pleiotropic activities in inhibiting inflammation, apoptosis, and oxidative stress in endothelial cells. Because endothelial progenitor cells (EPCs) play a significant role in vascular repair, we investigated whether kallistatin contributes to vascular regeneration by enhancing EPC migration and function. Methods and Results We examined the effect of endogenous kallistatin on circulating EPCs in a rat model of vascular injury and the mechanisms of kallistatin on EPC mobility and function in vitro. In deoxycorticosterone acetate–salt hypertensive rats, we found that kallistatin depletion augmented glomerular endothelial cell loss and diminished circulating EPC number, whereas kallistatin gene delivery increased EPC levels. In cultured EPCs, kallistatin significantly reduced tumor necrosis factor‐α–induced apoptosis and caspase‐3 activity, but kallistatin's effects were blocked by phosphoinositide 3‐kinase inhibitor (LY294002) and nitric oxide (NO) synthase inhibitor (l‐NAME). Kallistatin stimulated the proliferation, migration, adhesion and tube formation of EPCs; however, kallistatin's actions were abolished by LY294002, l‐NAME, endothelial NO synthase–small interfering RNA, constitutively active glycogen synthase kinase‐3β, or vascular endothelial growth factor antibody. Kallistatin also increased Akt, glycogen synthase kinase‐3β, and endothelial NO synthase phosphorylation; endothelial NO synthase, vascular endothelial growth factor, and matrix metalloproteinase‐2 synthesis and activity; and NO and vascular endothelial growth factor levels. Kallistatin's actions on phosphoinositide 3‐kinase–Akt signaling were blocked by LY294002, l‐NAME, and anti–vascular endothelial growth factor antibody. Conclusions Endogenous kallistatin plays a novel role in protection against vascular injury in hypertensive rats by promoting the mobility, viability, and vasculogenic capacity of EPCs via enhancing NO and vascular endothelial growth factor levels through activation of phosphoinositide 3‐kinase–Akt signaling. Kallistatin therapy may be a promising approach in the treatment of vascular diseases.
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Affiliation(s)
- Lin Gao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Pengfei Li
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Jingmei Zhang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Makoto Hagiwara
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Bo Shen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Grant Bledsoe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Eugene Chang
- Department of Obstetrics and Gynecology, College of Medicine, Medical University of South Carolina, Charleston, SC (E.C.)
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.)
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15
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Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93:1743-802. [PMID: 24137021 DOI: 10.1152/physrev.00006.2013] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
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Zhao X, Zhang W, Xing D, Li P, Fu J, Gong K, Hage FG, Oparil S, Chen YF. Endothelial cells overexpressing IL-8 receptor reduce cardiac remodeling and dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol 2013; 305:H590-8. [PMID: 23771691 PMCID: PMC3891247 DOI: 10.1152/ajpheart.00571.2012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 06/13/2013] [Indexed: 02/03/2023]
Abstract
The endothelium is a dynamic component of the cardiovascular system that plays an important role in health and disease. This study tested the hypothesis that targeted delivery of endothelial cells (ECs) overexpressing neutrophil membrane IL-8 receptors IL8RA and IL8RB reduces acute myocardial infarction (MI)-induced left ventricular (LV) remodeling and dysfunction and increases neovascularization in the area at risk surrounding the infarcted tissue. MI was created by ligating the left anterior descending coronary artery in 12-wk-old male Sprague-Dawley rats. Four groups of rats were studied: group 1: sham-operated rats without MI or EC transfusion; group 2: MI rats with intravenous vehicle; group 3: MI rats with transfused ECs transduced with empty adenoviral vector (Null-EC); and group 4: MI rats with transfused ECs overexpressing IL8RA/RB (1.5 × 10⁶ cells post-MI). Two weeks after MI, LV function was assessed by echocardiography; infarct size was assessed by triphenyltetrazolium chloride (live tissue) and picrosirus red (collagen) staining, and capillary density and neutrophil infiltration in the area at risk were measured by CD31 and MPO immunohistochemical staining, respectively. When compared with the MI + vehicle and MI-Null-EC groups, transfusion of IL8RA/RB-ECs decreased neutrophil infiltration and pro-inflammatory cytokine expression and increased capillary density in the area at risk, decreased infarct size, and reduced MI-induced LV dysfunction. These findings provide proof of principle that targeted delivery of ECs is effective in repairing injured cardiac tissue. Targeted delivery of ECs to infarcted hearts provides a potential novel strategy for the treatment of acute MI in humans.
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MESH Headings
- Adenoviridae/genetics
- Animals
- Cells, Cultured
- Disease Models, Animal
- Endothelial Cells/immunology
- Endothelial Cells/metabolism
- Endothelial Cells/transplantation
- Genetic Therapy/methods
- Genetic Vectors
- Immunohistochemistry
- Inflammation Mediators/metabolism
- Male
- Myocardial Infarction/genetics
- Myocardial Infarction/immunology
- Myocardial Infarction/metabolism
- Myocardial Infarction/pathology
- Myocardial Infarction/physiopathology
- Myocardial Infarction/therapy
- Myocardium/immunology
- Myocardium/metabolism
- Myocardium/pathology
- Neovascularization, Physiologic
- Neutrophil Infiltration
- Rats
- Rats, Sprague-Dawley
- Receptors, Interleukin-8/biosynthesis
- Receptors, Interleukin-8/genetics
- Recombinant Fusion Proteins/biosynthesis
- Time Factors
- Transduction, Genetic
- Transfection
- Up-Regulation
- Ventricular Dysfunction, Left/genetics
- Ventricular Dysfunction, Left/immunology
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/physiopathology
- Ventricular Dysfunction, Left/prevention & control
- Ventricular Function, Left
- Ventricular Remodeling
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Affiliation(s)
- Xiangmin Zhao
- Vascular Biology and Hypertension Program, Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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Yao Y, Sheng Z, Li Y, Fu C, Ma G, Liu N, Chao J, Chao L. Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis. J Transl Med 2013; 93:577-91. [PMID: 23508045 PMCID: PMC4051305 DOI: 10.1038/labinvest.2013.48] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Endothelial progenitor cells (EPCs) have been shown to enhance angiogenesis not only by incorporating into the vasculature but also by secreting cytokines, thereby serving as an ideal vehicle for gene transfer. As tissue kallikrein (TK) has pleiotropic effects in inhibiting apoptosis and oxidative stress, and promoting angiogenesis, we evaluated the salutary potential of kallikrein-modified human EPCs (hEPCs; Ad.hTK-hEPCs) after acute myocardial infarction (MI). We genetically modified hEPCs with a TK gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a nude mouse left anterior descending ligation model. hEPCs were manipulated to overexpress the TK gene. In vitro, the antiapoptotic and paracrine effects were assessed under oxidative stress. TK protects hEPCs from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and -9, induction of Akt phosphorylation, and secretion of vascular endothelial growth factor. In vivo, the Ad.hTK-hEPCs were transplanted after MI via intracardiac injection. The surviving cells were tracked after transplantation using near-infrared optical imaging. Left ventricular (LV) function was evaluated by transthoracic echocardiography. Capillary density was quantified using immunohistochemical staining. Engrafted Ad.hTK-hEPCs exhibited advanced protection against ischemia by increasing LV ejection fraction. Compared with Ad.Null-hEPCs, transplantation with Ad.hTK-hEPCs significantly decreased cardiomyocyte apoptosis in association with increased retention of transplanted EPCs in the myocardium. Capillary density and arteriolar density in the infarct border zone was significantly higher in Ad.hTK-hEPC-transplanted mice than in Ad.Null-hEPC-treated mice. Transplanted hEPCs were clearly incorporated into CD31(+) capillaries. These results indicate that implantation of kallikrein-modified EPCs in the heart provides advanced benefits in protection against ischemia-induced MI by enhanced angiogenesis and reducing apoptosis.
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Affiliation(s)
- Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
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Long J, Wang S, Zhang Y, Liu X, Zhang H, Wang S. The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model. J Vasc Surg 2013; 58:756-65.e2. [PMID: 23562340 DOI: 10.1016/j.jvs.2012.11.096] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 11/21/2012] [Accepted: 11/25/2012] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To explore the therapeutic potential of endothelial progenitor cells (EPCs) transfected with vascular endothelial growth factor A (VEGFA) and heme oxygenase-1 (HO-1) on rat hindlimb ischemia model. METHODS Eukaryotic expression vectors encoding VEGFA or HO-1 were constructed and introduced into EPCs isolated from rat bone marrow. In total, 150 Sprague Dawley rat hindlimb ischemia models were established and randomized into five groups which were injected via tail vein with phosphate-buffered saline (PBS), nontransfected EPCs, VEGFA-modified EPCs, HO-1-modified EPCs, and both VEGFA- and HO-1-modified EPCs, respectively. The microvessel density, the expressions of VEGFA and HO-1 in the ischemic limbs, the recovery of blood flow as evaluated by laser-Doppler perfusion imaging, and the rate of limb salvage were compared among different groups. RESULTS Transplantation of both VEGFA- and HO-1-modified EPCs in recipient rats significantly increased the microvessel density (expressed as capillaries/m(2) at day 21 after operation, group vascular endothelial growth factor (VEGF)+HO-1, 357 ± 14.1; group VEGF, 253.7 ± 9.9; group HO-1, 255.5 ± 12.5; group EPC, 210.7 ± 10.3; group PBS, 144.3 ± 9.3; P < .001), the expressions of VEGFA and HO-1 in ischemic tissue, the recovery of blood flow (at day 21, VEGF+HO-1 group, 85.4 ± 17.8%; VEGF group, 51.2 ± 13.2%; HO-1 group, 50.4 ± 12.9%; EPC group, 39.9 ± 8.5%; PBS group, 28.3 ± 7.8%; P < .001), and the rate of limb salvage (VEGF+HO-1 group, 94.4%; VEGF group or HO-1 group, 63.6%; EPC group, 50.0%; PBS group, 11.1%), compared with transplantation of either VEGFA- or HO-1-modified EPCs alone, or of nontransfected EPCs, or PBS injection. The order of therapeutic effectiveness on ischemic limbs was VEGFA- + HO-1-modifed EPC > either VEGFA- or HO-1-modified EPC alone > nontransfected EPC > PBS. CONCLUSIONS VEGFA-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in ischemic limbs of rat hindlimb ischemia model. In addition to VEGF, the introduction of HO-1 in EPC-based transplantation may serve as a novel and useful therapeutic strategy for ischemic disease of lower extremity.
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Affiliation(s)
- Jianting Long
- Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
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Sharma JN. Association between the kinin–forming system and cardiovascular pathophysiology. Asian Pac J Trop Biomed 2012. [DOI: 10.1016/s2221-1691(12)60523-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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