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Liu X, Pang S, Jiang Y, Wang L, Liu Y. The Role of Macrophages in Atherosclerosis: Participants and Therapists. Cardiovasc Drugs Ther 2025; 39:459-472. [PMID: 37864633 DOI: 10.1007/s10557-023-07513-5] [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] [Accepted: 10/08/2023] [Indexed: 10/23/2023]
Abstract
Currently, atherosclerosis, characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel, is considered to be a metabolic disease. As the most abundant innate immune cells in the body, macrophages play a key role in the onset, progression, or regression of atherosclerosis. For example, macrophages exhibit several polarization states in response to microenvironmental stimuli; an increasing proportion of macrophages, polarized toward M2, can suppress inflammation, scavenge cell debris and apoptotic cells, and contribute to tissue repair and fibrosis. Additionally, specific exosomes, generated by macrophages containing certain miRNAs and effective efferocytosis of macrophages, are crucial for atherosclerosis. Therefore, macrophages have emerged as a novel potential target for anti-atherosclerosis therapy. This article reviews the role of macrophages in atherosclerosis from different aspects: origin, phenotype, exosomes, and efferocytosis, and discusses new approaches for the treatment of atherosclerosis.
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Affiliation(s)
- Xiaoyu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shuchao Pang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
| | - Yangyang Jiang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lixin Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yi Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
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Zhang X, Liu S, Kong F, Shu L, Li Y, Wang D, Li L. Acidic polysaccharide from Ganoderma tsugae: Structural characterization and antiatherosclerotic related to macrophage polarization. Food Res Int 2025; 203:115913. [PMID: 40022418 DOI: 10.1016/j.foodres.2025.115913] [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: 10/24/2024] [Revised: 01/31/2025] [Accepted: 02/02/2025] [Indexed: 03/03/2025]
Abstract
Herein, a water-soluble Ganoderma tsugae acidic polysaccharide (GTP-2) was isolated and purified from the fruiting bodies of G. tsugae. GTP-2 has a molecular weight of 13.059 kDa, composed of →3)-β-d-Glcp-(1 → 3)-β-d-Glcp-(1 → 4)-GlcpUA-(1 → 4)-β-d-Glcp-1→ glucan backbone and branches ending with β-d-Glcp-(1 → 6)-β-d-Glcp-(1→, which is attached at C6 of →3,6)-β-d-Glcp-(1→. Subsequently, the antiatherosclerotic activity of GTP-2 was examined in apolipoprotein E deficient (ApoE-/-) mice fed with high-fat diet, and its potential mechanism of action was investigated. GTP-2 ameliorated blood lipid levels (total cholesterol, triglycerides, and low-density lipoprotein), while improving the serum levels of high-density lipoprotein. Furthermore, GTP-2 alleviated the atherosclerotic lesions and reduced levels of inflammatory cytokines. Analysis of the gut microbiota revealed that GTP-2 enhanced the abundance of beneficial bacteria (Lactobacillu and Akkermansia). The serum metabolite composition was further altered, with a significant reduction in octadecanoic acid level. GTP-2 regulated the nuclear factor kappa-B signaling pathway by inhibiting macrophage polarization to M1 phenotype. Collectively, these findings support the potential use of GTP-2 as an antiatherosclerotic therapy.
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Affiliation(s)
- Xin Zhang
- College of Horticulture, Shenyang Agricultural University, Shenyang 110866 China; Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China.
| | - Shuai Liu
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China; College of Plant Protection, Jilin Agricultural University, Changchun 130118 China.
| | - Fange Kong
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China; College of Plant Protection, Jilin Agricultural University, Changchun 130118 China.
| | - Lili Shu
- College of Horticulture, Shenyang Agricultural University, Shenyang 110866 China.
| | - Yu Li
- College of Horticulture, Shenyang Agricultural University, Shenyang 110866 China; Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China.
| | - Di Wang
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China; College of Plant Protection, Jilin Agricultural University, Changchun 130118 China.
| | - Lanzhou Li
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118 China; College of Plant Protection, Jilin Agricultural University, Changchun 130118 China.
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Wu Y, Xu Y, Xu L. Pharmacological therapy targeting the immune response in atherosclerosis. Int Immunopharmacol 2024; 141:112974. [PMID: 39168023 DOI: 10.1016/j.intimp.2024.112974] [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: 06/12/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 08/23/2024]
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease characterized by the formation of atherosclerotic plaques that consist of numerous cells including smooth muscle cells, endothelial cells, immune cells, and foam cells. The most abundant innate and adaptive immune cells, including neutrophils, monocytes, macrophages, B cells, and T cells, play a pivotal role in the inflammatory response, lipoprotein metabolism, and foam cell formation to accelerate atherosclerotic plaque formation. In this review, we have discussed the underlying mechanisms of activated immune cells in promoting AS and reviewed published clinical trials for the treatment of AS by suppressing immune cell activation. We have also presented some crucial shortcomings of current clinical trials. Lastly, we have discussed the therapeutic potential of novel compounds, including herbal medicine and dietary food, in alleviating AS in animals. Despite these limitations, further clinical trials and experimental studies will enhance our understanding of the mechanisms modulated by immune cells and promote widespread drug use to treat AS by suppressing immune system-induced inflammation.
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Affiliation(s)
- Yirong Wu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China
| | - Yizhou Xu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China.
| | - Linhao Xu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Translational Medicine Research Center, Hangzhou First People's Hospital, Hangzhou 310006, Zhejiang, China.
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Mohammadi S, Al-Harrasi A. Macrophage modulation with dipeptidyl peptidase-4 inhibitors: A new frontier for treating diabetic cardiomyopathy? World J Diabetes 2024; 15:1847-1852. [PMID: 39280186 PMCID: PMC11372644 DOI: 10.4239/wjd.v15.i9.1847] [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: 04/01/2024] [Revised: 05/13/2024] [Accepted: 06/13/2024] [Indexed: 08/27/2024] Open
Abstract
This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy (DCM) treatment by dipeptidyl peptidase-4 (DPP-4) inhibitors. Zhang et al studied teneligliptin, a DPP-4 inhibitor used for diabetes management, and its potential cardioprotective effects in a diabetic mouse model. They suggested teneligliptin administration may reverse established markers of DCM, including cardiac hypertrophy and compromised function. It also inhibited the NLRP3 inflammasome and reduced inflammatory cytokine production in diabetic mice. Macrophages play crucial roles in DCM pathogenesis. Chronic hyperglycemia disturbs the balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, favoring a pro-inflammatory state contributing to heart damage. Here, we highlight the potential of DPP-4 inhibitors to modulate macrophage function and promote an anti-inflammatory environment. These compounds may achieve this by elevating glucagon-like peptide-1 levels and potentially inhibiting the NLRP3 inflammasome. Further studies on teneligliptin in combination with other therapies targeting different aspects of DCM could be suggested for developing more effective treatment strategies to improve cardiovascular health in diabetic patients.
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Affiliation(s)
- Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
- Department of Biological Sciences and Chemistry, University of Nizwa, Nizwa 616, Oman
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Suenaga A, Sawa N, Oba Y, Ikuma D, Sekine A, Yamanouchi M, Hasegawa E, Mizuno H, Suwabe T, Hayashi N, Kono K, Kinowaki K, Ohashi K, Miyazono M, Yamaguchi Y, Ubara Y. A case of bullous pemphigoid and renal disease after dipeptidyl peptidase 4 inhibitor administration. CEN Case Rep 2024; 13:264-270. [PMID: 38055184 PMCID: PMC11294501 DOI: 10.1007/s13730-023-00835-1] [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: 09/01/2023] [Accepted: 10/29/2023] [Indexed: 12/07/2023] Open
Abstract
A 62-year-old man with type 2 diabetes was admitted because of a decrease in estimated glomerular filtration rate from 72 to 17.5 mL/min/1.73 m2 in 10 years and development of widespread bullous skin lesions. His hemoglobin A1c level had been maintained at 6.0-7.0% for 10 years with a dipeptidyl peptidase (DPP)-4 inhibitor. Skin biopsy showed typical bullous pemphigoid, and kidney biopsy showed tubulointerstitial nephritis with eosinophilic infiltration and glomerular endothelial cell proliferation. After discontinuing the DPP-4 inhibitor, skin lesions improved, and renal decline slowed. This case indicates that DPP-4 inhibitors can cause not only skin lesions but also renal disease.
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Affiliation(s)
- Atsuhiko Suenaga
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan.
- Department of Nephrology, Saga University Internal Medicine, Saga, Japan.
| | - Naoki Sawa
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yuki Oba
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Daisuke Ikuma
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Akinari Sekine
- Department of Nephrology and Rheumatology, Toranomon Hospital, Tokyo, Japan
| | - Masayuki Yamanouchi
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Eiko Hasegawa
- Department of Nephrology and Rheumatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Hiroki Mizuno
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Tatsuya Suwabe
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | | | - Kei Kono
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | | | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
- Department of Human Pathology, Tokyo Medical Dental University, Tokyo, Japan
| | - Motoaki Miyazono
- Department of Nephrology, Saga University Internal Medicine, Saga, Japan
| | | | - Yoshifumi Ubara
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Chen R, Zhang H, Tang B, Luo Y, Yang Y, Zhong X, Chen S, Xu X, Huang S, Liu C. Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:130. [PMID: 38816371 PMCID: PMC11139930 DOI: 10.1038/s41392-024-01840-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 04/02/2024] [Accepted: 04/21/2024] [Indexed: 06/01/2024] Open
Abstract
The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
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Affiliation(s)
- Runkai Chen
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Hongrui Zhang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Botao Tang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yukun Luo
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yufei Yang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Xin Zhong
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Sifei Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Xinjie Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Shengkang Huang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Canzhao Liu
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China.
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Luo M, Zhao F, Cheng H, Su M, Wang Y. Macrophage polarization: an important role in inflammatory diseases. Front Immunol 2024; 15:1352946. [PMID: 38660308 PMCID: PMC11039887 DOI: 10.3389/fimmu.2024.1352946] [Citation(s) in RCA: 73] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.
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Affiliation(s)
| | | | | | | | - Yuanmin Wang
- The Third Affiliated Hospital of Zunyi Medical University, The First People’s Hospital of Zunyi, Zunyi, Guizhou, China
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Youssef N, Noureldein MH, Riachi ME, Haddad A, Eid AA. Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression. Am J Physiol Renal Physiol 2024; 326:F301-F312. [PMID: 38153850 DOI: 10.1152/ajprenal.00266.2023] [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: 08/30/2023] [Revised: 11/29/2023] [Accepted: 12/16/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.
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Affiliation(s)
- Natalie Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed H Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mansour E Riachi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Antony Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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Otunla AA, Shanmugarajah K, Davies AH, Lucia Madariaga M, Shalhoub J. The Biological Parallels Between Atherosclerosis and Cardiac Allograft Vasculopathy: Implications for Solid Organ Chronic Rejection. Cardiol Rev 2024; 32:2-11. [PMID: 38051983 DOI: 10.1097/crd.0000000000000437] [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] [Indexed: 11/25/2022]
Abstract
Atherosclerosis and solid organ chronic rejection are pervasive chronic disease states that account for significant morbidity and mortality in developed countries. Recently, a series of shared molecular pathways have emerged, revealing biological parallels from early stages of development up to the advanced forms of pathology. These shared mechanistic processes are inflammatory in nature, reflecting the importance of inflammation in both disorders. Vascular inflammation triggers endothelial dysfunction and disease initiation through aberrant vasomotor control and shared patterns of endothelial activation. Endothelial dysfunction leads to the recruitment of immune cells and the perpetuation of the inflammatory response. This drives lesion formation through the release of key cytokines such as IFN-y, TNF-alpha, and IL-2. Continued interplay between the adaptive and innate immune response (represented by T lymphocytes and macrophages, respectively) promotes lesion instability and thrombotic complications; hallmarks of advanced disease in both atherosclerosis and solid organ chronic rejection. The aim of this study is to identify areas of overlap between atherosclerosis and chronic rejection. We then discuss new approaches to improve current understanding of the pathophysiology of both disorders, and eventually design novel therapeutics.
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Affiliation(s)
- Afolarin A Otunla
- From the Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | | | - Alun H Davies
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
| | | | - Joseph Shalhoub
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
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Suenaga A, Sawa N, Oba Y, Ikuma D, Sekine A, Hasegawa E, Mizuno H, Suwabe T, Ikeda S, Tsujimoto T, Kono K, Shintani-Domoto Y, Kinowaki K, Ohashi K, Miyazono M, Yamaguchi Y, Ubara Y. Dipeptidyl peptidase-4 inhibitor-related renal disease. J Diabetes Complications 2023; 37:108590. [PMID: 37678056 DOI: 10.1016/j.jdiacomp.2023.108590] [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: 05/08/2023] [Revised: 07/29/2023] [Accepted: 08/19/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. METHODS Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). RESULTS Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of -11.2 (-17.6, -9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of -1.6 (-3.1, -0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. CONCLUSION DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.
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Affiliation(s)
- Atsuhiko Suenaga
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan; Department of Nephrology, Saga University School of Medicine, Saga, Japan.
| | - Naoki Sawa
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan; Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yuki Oba
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Daisuke Ikuma
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Akinari Sekine
- Department of Nephrology and Rheumatology, Toranomon Hospital, Tokyo, Japan
| | - Eiko Hasegawa
- Department of Nephrology and Rheumatology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Hiroki Mizuno
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Tatsuya Suwabe
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Sara Ikeda
- Department of Diabetes and Endocrinology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Tetsuro Tsujimoto
- Department of Diabetes and Endocrinology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Kei Kono
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | | | | | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan; Department of Human Pathology, Tokyo Medical Dental University, Tokyo, Japan
| | - Motoaki Miyazono
- Department of Nephrology, Saga University School of Medicine, Saga, Japan
| | | | - Yoshifumi Ubara
- Department of Nephrology and Rheumatology, Toranomon Hospital Kajigaya, Kanagawa, Japan; Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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11
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Kiseleva V, Vishnyakova P, Elchaninov A, Fatkhudinov T, Sukhikh G. Biochemical and molecular inducers and modulators of M2 macrophage polarization in clinical perspective. Int Immunopharmacol 2023; 122:110583. [PMID: 37423155 DOI: 10.1016/j.intimp.2023.110583] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/24/2023] [Accepted: 06/26/2023] [Indexed: 07/11/2023]
Abstract
Macrophages as innate immune cells with great plasticity are of great interest for cell therapy. There are two main macrophage populations - pro- and anti-inflammatory cells also known as M1 and M2. High potential in cancer research contributed to the in-depth study of the molecular processes leading to the polarization of macrophages into the M1 phenotype, and much less attention has been paid to anti-inflammatory M2 macrophages, which can be successfully used in cell therapy of inflammatory diseases. This review describes ontogenesis of macrophages, main functions of pro- and and-inflammatory cells and four M2 subpopulations characterized by different functionalities. Data on agents (cytokines, microRNAs, drugs, plant extracts) that may induce M2 polarization through the changes in microenvironment, metabolism, and efferocytosis are summarized. Finally, recent attempts at stable macrophage polarization using genetic modifications are described. This review may be helpful for researchers concerned with the problem of M2 macrophage polarization and potential use of these anti-inflammatory cells for the purposes of regenerative medicine.
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Affiliation(s)
- Viktoriia Kiseleva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia; Peoples' Friendship University of Russia, Moscow, Russia.
| | - Polina Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia; Peoples' Friendship University of Russia, Moscow, Russia
| | - Andrey Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia; Peoples' Friendship University of Russia, Moscow, Russia; Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution "Petrovsky National Research Centre of Surgery", Moscow, Russia
| | - Timur Fatkhudinov
- Peoples' Friendship University of Russia, Moscow, Russia; Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution "Petrovsky National Research Centre of Surgery", Moscow, Russia
| | - Gennady Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia
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12
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Galindo CL, Khan S, Zhang X, Yeh YS, Liu Z, Razani B. Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets. Expert Opin Ther Targets 2023; 27:1231-1245. [PMID: 38009300 PMCID: PMC10843715 DOI: 10.1080/14728222.2023.2288272] [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: 06/28/2023] [Accepted: 11/22/2023] [Indexed: 11/28/2023]
Abstract
INTRODUCTION Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide. AREAS COVERED Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development. EXERT OPINION As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.
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Affiliation(s)
- Cristi L. Galindo
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Saifur Khan
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Xiangyu Zhang
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Yu-Sheng Yeh
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Ziyang Liu
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Babak Razani
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
- Pittsburgh VA Medical Center, Pittsburgh, PA
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13
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Markina YV, Kirichenko TV, Tolstik TV, Bogatyreva AI, Zotova US, Cherednichenko VR, Postnov AY, Markin AM. Target and Cell Therapy for Atherosclerosis and CVD. Int J Mol Sci 2023; 24:10308. [PMID: 37373454 DOI: 10.3390/ijms241210308] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Cardiovascular diseases (CVD) and, in particular, atherosclerosis, remain the main cause of death in the world today. Unfortunately, in most cases, CVD therapy begins after the onset of clinical symptoms and is aimed at eliminating them. In this regard, early pathogenetic therapy for CVD remains an urgent problem in modern science and healthcare. Cell therapy, aimed at eliminating tissue damage underlying the pathogenesis of some pathologies, including CVD, by replacing it with various cells, is of the greatest interest. Currently, cell therapy is the most actively developed and potentially the most effective treatment strategy for CVD associated with atherosclerosis. However, this type of therapy has some limitations. In this review, we have tried to summarize the main targets of cell therapy for CVD and atherosclerosis in particular based on the analysis using the PubMed and Scopus databases up to May 2023.
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Affiliation(s)
- Yuliya V Markina
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Taisiya V Tolstik
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Ulyana S Zotova
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Anton Yu Postnov
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | - Alexander M Markin
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
- Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN University), Moscow 117198, Russia
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14
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Shen L, Chen W, Ding J, Shu G, Chen M, Zhao Z, Xia S, Ji J. The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques. FASEB J 2023; 37:e22791. [PMID: 36723768 DOI: 10.1096/fj.202201486r] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 01/03/2023] [Accepted: 01/12/2023] [Indexed: 02/02/2023]
Abstract
Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.
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Affiliation(s)
- Lin Shen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Weiyue Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Jiayi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Gaofeng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Shuiwei Xia
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
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15
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Amin SN, Sakr HI, El Gazzar WB, Shaltout SA, Ghaith HS, Elberry DA. Combined saline and vildagliptin induced M2 macrophage polarization in hepatic injury induced by acute kidney injury. PeerJ 2023; 11:e14724. [PMID: 36815993 PMCID: PMC9933746 DOI: 10.7717/peerj.14724] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/19/2022] [Indexed: 02/15/2023] Open
Abstract
Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into "classically activated macrophages" (M1) and "alternatively activated macrophages" (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.
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Affiliation(s)
- Shaimaa N. Amin
- Department of Anatomy, Physiology, and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt,Department of Medical Physiology, Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Walaa B. El Gazzar
- Department of Anatomy, Physiology, and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Sherif A. Shaltout
- Department of Pharmacology, Public health, and Clinical Skills, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Dalia A. Elberry
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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16
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Macrophage Phenotyping in Atherosclerosis by Proteomics. Int J Mol Sci 2023; 24:ijms24032613. [PMID: 36768933 PMCID: PMC9917096 DOI: 10.3390/ijms24032613] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Macrophages are heterogeneous and plastic cells, able to adapt their phenotype and functions to changes in the microenvironment. They are involved in several homeostatic processes and also in many human diseases, including atherosclerosis, where they participate in all the stages of the disease. For these reasons, macrophages have been studied extensively using different approaches, including proteomics. Proteomics, indeed, may be a powerful tool to better understand the behavior of these cells, and a careful analysis of the proteome of different macrophage phenotypes can help to better characterize the role of these phenotypes in atherosclerosis and provide a broad view of proteins that might potentially affect the course of the disease. In this review, we discuss the different proteomic techniques that have been used to delineate the proteomic profile of macrophage phenotypes and summarize some results that can help to elucidate the roles of macrophages and develop new strategies to counteract the progression of atherosclerosis and/or promote regression.
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17
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Wu J, He S, Song Z, Chen S, Lin X, Sun H, Zhou P, Peng Q, Du S, Zheng S, Liu X. Macrophage polarization states in atherosclerosis. Front Immunol 2023; 14:1185587. [PMID: 37207214 PMCID: PMC10189114 DOI: 10.3389/fimmu.2023.1185587] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 04/21/2023] [Indexed: 05/21/2023] Open
Abstract
Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xiu Liu
- *Correspondence: Xiu Liu, ; Shaoyi Zheng,
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18
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Xie Y, Chen H, Qu P, Qiao X, Guo L, Liu L. Novel insight on the role of Macrophages in atherosclerosis: Focus on polarization, apoptosis and efferocytosis. Int Immunopharmacol 2022; 113:109260. [DOI: 10.1016/j.intimp.2022.109260] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/13/2022] [Indexed: 11/05/2022]
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19
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Chen SY, Kong XQ, Zhang KF, Luo S, Wang F, Zhang JJ. DPP4 as a Potential Candidate in Cardiovascular Disease. J Inflamm Res 2022; 15:5457-5469. [PMID: 36147690 PMCID: PMC9488155 DOI: 10.2147/jir.s380285] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/09/2022] [Indexed: 11/23/2022] Open
Abstract
The rising prevalence of cardiovascular disease has become a global health concern. The occurrence of cardiovascular disease is the result of long-term interaction of many risk factors, one of which is diabetes. As a novel anti-diabetic drug, DPP4 inhibitor has been proven to be cardiovascular safe in five recently completed cardiovascular outcome trials. Accumulating studies suggest that DPP4 inhibitor has potential benefits in a variety of cardiovascular diseases, including hypertension, calcified aortic valve disease, coronary atherosclerosis, and heart failure. On the one hand, in addition to improving blood glucose control, DPP4 inhibitor is involved in controlling cardiovascular risk factors. On the other hand, DPP4 inhibitor directly regulates the occurrence and progression of cardiovascular diseases through a variety of mechanisms. In this review, we summarize the recent advances of DPP4 in cardiovascular disease, aiming to discuss DPP4 inhibitor as a potential option for cardiovascular therapy.
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Affiliation(s)
- Si-Yu Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiang-Quan Kong
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Cardiology, Nanjing Heart Centre, Nanjing, People's Republic of China
| | - Ke-Fan Zhang
- Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Shuai Luo
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Feng Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Jun-Jie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Cardiology, Nanjing Heart Centre, Nanjing, People's Republic of China
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20
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Enhanced macrophage polarization induced by COX-2 inhibitor-loaded Pd octahedral nanozymes for treatment of atherosclerosis. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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21
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Nasser SA, Afify EA, Kobeissy F, Hamam B, Eid AH, El-Mas MM. Inflammatory Basis of Atherosclerosis: Modulation by Sex Hormones. Curr Pharm Des 2021; 27:2099-2111. [PMID: 33480335 DOI: 10.2174/1381612827666210122142811] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/17/2020] [Indexed: 11/22/2022]
Abstract
Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of death globally. Several lines of evidence are supportive of the contributory role of vascular inflammation in atherosclerosis. Diverse immune cell types, including monocytes/macrophages, T-cells and neutrophils, as well as specialized proresolving lipid mediators, have been successfully characterized as key players in vascular inflammation. The increased prevalence of atherosclerotic CVD in men in comparison to age-matched premenopausal women and the abolition of sex differences in prevalence during menopause strongly suggest a pivotal role of sex hormones in the development of CVD. Indeed, many animal and human studies conclusively implicate sex hormones as a crucial component in driving the immune response. This is further corroborated by the effective identification of sex hormone receptors in vascular endothelial cells, vascular smooth muscle cells and immune cells. Collectively, these findings suggest a cellular communication between sex hormones and vascular or immune cells underlying the vascular inflammation in atherosclerosis. The aim of this review is to provide an overview of vascular inflammation as a causal cue underlying atherosclerotic CVDs within the context of the modulatory effects of sex hormones. Moreover, the cellular and molecular signaling pathways underlying the sex hormones- immune system interactions as potential culprits for vascular inflammation are highlighted with detailed and critical discussion. Finally, the review concludes by speculations on the potential sex-related efficacy of currently available immunotherapies in mitigating vascular inflammation. Conceivably, a deeper understanding of the immunoregulatory influence of sex hormones on vascular inflammation-mediated atherosclerosis permits sex-based management of atherosclerosis-related CVDs.
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Affiliation(s)
- Suzanne A Nasser
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, P.O. Box 11-5020, Beirut, Lebanon
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, American University of Beirut, P.O. Box 11-0236, Beirut, Lebanon
| | - Bassam Hamam
- Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, P.O. Box 146404, Beirut, Lebanon
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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22
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Abstract
Atherosclerosis is the leading cause of acute cardiovascular events, and vascular calcification is an important pathological phenomenon in atherosclerosis. Recently, many studies have shown that immune cells are closely associated with the development of atherosclerosis and calcification, but there are many conflicting viewpoints because of immune system complications, such as the pro-atherosclerotic and atheroprotective effects of regulatory B cells (Bregs), T helper type 2 (Th2) cells and T helper type 17 (Th17) cells. In this review, we summarize the studies on the roles of immune cells, especially lymphocytes and macrophages, in atherosclerotic calcification. Furthermore, we prepared graphs showing the relationship between T cells, B cells and macrophages and atherosclerotic calcification. Finally, we highlight some potential issues that are closely associated with the function of immune cells in atherosclerotic calcification. Based on current research results, this review summarizes the relationship between immune cells and atherosclerotic calcification, and it will be beneficial to understand the relationship of immune cells and atherosclerotic calcification.
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Affiliation(s)
- Jingsong Cao
- Clinical Medicine Research Center, 574417The First Affiliated Hospital of University of South China, Hengyang, China.,Department of Endocrinology and Metabolism, 574417The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Xuyu Zu
- Clinical Medicine Research Center, 574417The First Affiliated Hospital of University of South China, Hengyang, China
| | - Jianghua Liu
- Clinical Medicine Research Center, 574417The First Affiliated Hospital of University of South China, Hengyang, China.,Department of Endocrinology and Metabolism, 574417The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.,Department of Metabolism and Endocrinology, 574417The First Affiliated Hospital of University of South China, Hengyang, China
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23
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Lin P, Ji HH, Li YJ, Guo SD. Macrophage Plasticity and Atherosclerosis Therapy. Front Mol Biosci 2021; 8:679797. [PMID: 34026849 PMCID: PMC8138136 DOI: 10.3389/fmolb.2021.679797] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/12/2021] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a chronic disease starting with the entry of monocytes into the subendothelium and the subsequent differentiation into macrophages. Macrophages are the major immune cells in atherosclerotic plaques and are involved in the dynamic progression of atherosclerotic plaques. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition, and stability. The heterogenicity and plasticity of atherosclerotic macrophages have been a hotspot in recent years. Studies demonstrated that lipids, cytokines, chemokines, and other molecules in the atherosclerotic plaque microenvironment regulate macrophage phenotype, contributing to the switch of macrophages toward a pro- or anti-atherosclerosis state. Of note, M1/M2 classification is oversimplified and only represent two extreme states of macrophages. Moreover, M2 macrophages in atherosclerosis are not always protective. Understanding the phenotypic diversity and functions of macrophages can disclose their roles in atherosclerotic plaques. Given that lipid-lowering therapy cannot completely retard the progression of atherosclerosis, macrophages with high heterogeneity and plasticity raise the hope for atherosclerosis regression. This review will focus on the macrophage phenotypic diversity, its role in the progression of the dynamic atherosclerotic plaque, and finally discuss the possibility of treating atherosclerosis by targeting macrophage microenvironment.
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Affiliation(s)
- Ping Lin
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hong-Hai Ji
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yan-Jie Li
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Shou-Dong Guo
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
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24
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Cao F, Wu K, Zhu YZ, Bao ZW. Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging. Front Endocrinol (Lausanne) 2021; 12:731273. [PMID: 34489872 PMCID: PMC8416540 DOI: 10.3389/fendo.2021.731273] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 07/21/2021] [Indexed: 12/22/2022] Open
Abstract
Vascular aging is characterized by alterations in the constitutive properties and biological functions of the blood vessel wall. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are indispensability elements in the inner layer and the medial layer of the blood vessel wall, respectively. Dipeptidyl peptidase-4 (DPP4) inhibitors, as a hypoglycemic agent, play a protective role in reversing vascular aging regardless of their effects in meliorating glycemic control in humans and animal models of type 2 diabetes mellitus (T2DM) through complex cellular mechanisms, including improving EC dysfunction, promoting EC proliferation and migration, alleviating EC senescence, obstructing EC apoptosis, suppressing the proliferation and migration of VSMCs, increasing circulating endothelial progenitor cell (EPC) levels, and preventing the infiltration of mononuclear macrophages. All of these showed that DPP4 inhibitors may exert a positive effect against vascular aging, thereby preventing vascular aging-related diseases. In the current review, we will summarize the cellular mechanism of DPP4 inhibitors regulating vascular aging; moreover, we also intend to compile the roles and the promising therapeutic application of DPP4 inhibitors in vascular aging-related diseases.
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Affiliation(s)
- Fen Cao
- Department of Cardiology, Huaihua First People’s Hospital, Huaihua, China
| | - Kun Wu
- Department of Neurology, Huaihua First People’s Hospital, Huaihua, China
| | - Yong-Zhi Zhu
- Department of Cardiology, Huaihua First People’s Hospital, Huaihua, China
| | - Zhong-Wu Bao
- Department of Cardiology, Huaihua First People’s Hospital, Huaihua, China
- *Correspondence: Zhong-Wu Bao,
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Al-Mallah MH, Hyafil F, Santulli G. No pleotropic effects of linagliptin on atherosclerotic plaques: Case closed. Atherosclerosis 2020; 305:61-63. [PMID: 32561072 DOI: 10.1016/j.atherosclerosis.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/05/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Mouaz H Al-Mallah
- Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.
| | - Fabien Hyafil
- Department of Nuclear Medicine, Centre Hospitalier Universitaire Bichat, Assistance Publique - Hôpitaux de Paris, Inserm 1148, Université Paris Diderot, Paris, France
| | - Gaetano Santulli
- Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, USA; Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), The "Norman Fleischer" Institute for Diabetes and Metabolism (FIDAM), New York, NY, USA
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Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis. Int J Mol Sci 2020; 21:ijms21072275. [PMID: 32218354 PMCID: PMC7177465 DOI: 10.3390/ijms21072275] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/13/2022] Open
Abstract
Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 (Glucagon-like peptide-1) and GIP (Gastric inhibitors polypeptide) and prolong their action. Some studies present results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin reaching beyond glycemic control. Vildagliptin is able to limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α), IL-1β (Interleukin-1β), and IL-8 (Interleukin 8). Moreover, vildagliptin regulates lipid metabolism; attenuates postprandial hypertriglyceridemia; and lowers serum triglycerides, apolipoprotein B, and blood total cholesterol levels. This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. Vildagliptin reduces vascular stiffness via elevation of nitric oxide synthesis, improves vascular relaxation, and results in reduction in both systolic and diastolic blood pressure. Treatment with vildagliptin lowers the level of PAI-1 presenting possible antithrombotic effect. By affecting the endothelium, inflammation, and lipid metabolism, vildagliptin may affect the development of atherosclerosis at its various stages. The article presents a summary of the studies assessing vasculoprotective effects of vildagliptin with special emphasis on atherogenesis.
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Liu H, Guo L, Xing J, Li P, Sang H, Hu X, Du Y, Zhao L, Song R, Gu H. The protective role of DPP4 inhibitors in atherosclerosis. Eur J Pharmacol 2020; 875:173037. [PMID: 32097656 DOI: 10.1016/j.ejphar.2020.173037] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 01/30/2020] [Accepted: 02/21/2020] [Indexed: 12/16/2022]
Abstract
Diabetes is a chronic non-communicable disease whose incidence continues to grow rapidly, and it is one of the most serious and critical public health problems. Diabetes complications, especially atherosclerosis-related chronic vascular complications, are a serious threat to human life and health. Growing evidence suggests that dipeptidyl peptidase 4 (DPP4) inhibitors, beyond their role in improving glycemic control, are helpful in ameliorating endothelial dysfunction in humans and animal models of T2DM. In fact, DPP4 inhibitors have been shown by successive studies to play a protective effect against vascular complications. On one hand, in addition to their hypoglycemic effects, DPP4 inhibitors participate in the control of atherosclerotic risk factors by regulating blood lipids and lowering blood pressure. On the other hand, DPP4 inhibitors exert anti-atherosclerotic effects directly through multiple mechanisms, including improving endothelial cell dysfunction, increasing circulating endothelial progenitor cell (EPCs) levels, regulating mononuclear macrophages and smooth muscle cells, inhibiting inflammation and oxidative stress and improving plaque instability. Herein, we review the beneficial roles of DPP4 inhibitors in atherosclerosis as detailed.
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Affiliation(s)
- Hengdao Liu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Lingli Guo
- Department of General Medicine, The Third People's Provincial Hospital of Henan Province, Zhengzhou, 450000, Henan, China
| | - Junhui Xing
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Peicheng Li
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University. Xinxiang, Henan, 453100, China
| | - Haiqiang Sang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xiaofang Hu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (Xiangya), Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yunpeng Du
- Department of Cardiology, Huixian People's Hospital, Xinxiang, Henan, 453600, China
| | - Liangping Zhao
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University. Xinxiang, Henan, 453100, China
| | - Ruipeng Song
- Department of Endocrinology, The Third People's Provincial Hospital of Henan Province, Zhengzhou, 450000, Henan, China.
| | - Heping Gu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
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Nishida S, Matsumura T, Senokuchi T, Murakami-Nishida S, Ishii N, Morita Y, Yagi Y, Motoshima H, Kondo T, Araki E. Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions. Biochem Biophys Res Commun 2020; 524:8-15. [PMID: 31964532 DOI: 10.1016/j.bbrc.2020.01.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 01/06/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control. RESULTS In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.
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Affiliation(s)
- Shuhei Nishida
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takeshi Matsumura
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
| | - Takafumi Senokuchi
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Saiko Murakami-Nishida
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Norio Ishii
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yutaro Morita
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshitaka Yagi
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroyuki Motoshima
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Tatsuya Kondo
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular Macrophages in Atherosclerosis. J Immunol Res 2019; 2019:4354786. [PMID: 31886303 PMCID: PMC6914912 DOI: 10.1155/2019/4354786] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/19/2019] [Accepted: 10/23/2019] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis is the main pathological basis for the occurrence of most cardiovascular diseases, the leading global health threat, and a great burden for society. It has been well established that atherosclerosis is not only a metabolic disorder but also a chronic, sterile, and maladaptive inflammatory process encompassing both innate and adaptive immunity. Macrophages, the major immune cell population in atherosclerotic lesions, have been shown to play critical roles in all stages of atherosclerosis, including the initiation and progression of advanced atherosclerosis. Macrophages have emerged as a novel potential target for antiatherosclerosis therapy. In addition, the macrophage phenotype is greatly influenced by microenvironmental stimuli in the plaques and presents complex heterogeneity. This article reviews the functions of macrophages in different stages of atherosclerosis, as well as the phenotypes and functions of macrophage subsets. New treatment strategies based on macrophage-related inflammation are also discussed.
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Affiliation(s)
- Hailin Xu
- Department of General Surgery, The First People's Hospital of Jiande, Hangzhou, China
| | - Jingxin Jiang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wuzhen Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Wenlu Li
- Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Zhigang Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
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Yang S, Yuan HQ, Hao YM, Ren Z, Qu SL, Liu LS, Wei DH, Tang ZH, Zhang JF, Jiang ZS. Macrophage polarization in atherosclerosis. Clin Chim Acta 2019; 501:142-146. [PMID: 31730809 DOI: 10.1016/j.cca.2019.10.034] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/23/2019] [Accepted: 10/23/2019] [Indexed: 12/20/2022]
Abstract
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.
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Affiliation(s)
- Sai Yang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Hou-Qin Yuan
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Ya-Meng Hao
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Shun-Lin Qu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Lu-Shan Liu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Dang-Heng Wei
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Zhi-Han Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Ji-Feng Zhang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Rd, NCRC Bldg26-357S, Ann Arbor, MI 48109, USA
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang City, Hunan Province, 421001, PR China.
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Nguyen PA, Won JS, Rahman MK, Bae EJ, Cho MK. Modulation of Sirt1/NF-κB interaction of evogliptin is attributed to inhibition of vascular inflammatory response leading to attenuation of atherosclerotic plaque formation. Biochem Pharmacol 2019; 168:452-464. [DOI: 10.1016/j.bcp.2019.08.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/12/2019] [Indexed: 12/11/2022]
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Tasanen K, Varpuluoma O, Nishie W. Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Front Immunol 2019; 10:1238. [PMID: 31275298 PMCID: PMC6593303 DOI: 10.3389/fimmu.2019.01238] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/16/2019] [Indexed: 12/18/2022] Open
Abstract
Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated blistering skin disease that mainly affects the elderly. Typical clinical features include the widespread blisters, often preceded by and/or associated with itchy urticarial or eczema-like lesions. BP patients have circulating autoantibodies against BP180 and/or the plakin family protein BP230 both of which are components of hemidesmosomes in basal keratinocytes. Most BP autoantibodies particularly target the epitopes within the non-collagenous NC16A domain of BP180. Clinical findings and murine models of BP have provided evidence of a pathogenic role of anti-NC16A autoantibodies. However, it is largely unknown what triggers the breakage of immunotolerance against BP180 in elderly individuals. The incidence of BP has been increased over the past two decades in several countries. Aside from aging populations, the factors behind this phenomenon are still not fully understood. Neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, and certain dementias are independent risk factors for BP. Recently several case reports have described BP in patients with diabetes mellitus (DM) patients who have been treated with dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins), which are a widely used class of anti-DM drugs. The association between the use of DPP-4is, particularly vildagliptin, and BP risk has been confirmed by several epidemiological studies. Evidence suggests that cases of gliptin-associated BP in Japan display certain features that set them apart from cases of “regular” BP. These include a “non-inflammatory” phenotype, targeting by antibodies of different immunodominant BP180 epitopes, and a specific association with the human leukocyte antigen (HLA) types. However, recent studies in European populations have found no major differences between the clinical and immunological characteristics of gliptin-associated BP and “regular” BP. The DPP-4 protein (also known as CD26) is ubiquitously expressed and has multiple functions in various cell types. The different effects of the inhibition of DPP-4/CD26 activity include, for example, tissue modeling and regulation of inflammatory cells such as T lymphocytes. Although the pathomechanism of gliptin-associated BP is currently largely unknown, investigation of the unique effect of gliptins in the induction of BP may provide a novel route to better understanding of how immunotolerance against BP180 breaks down in BP.
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Affiliation(s)
- Kaisa Tasanen
- PEDEGO Research Unit, Department of Dermatology, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Outi Varpuluoma
- PEDEGO Research Unit, Department of Dermatology, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Wataru Nishie
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Dipeptidyl dipeptidase-4 inhibitor recovered ischemia through an increase in vasculogenic endothelial progenitor cells and regeneration-associated cells in diet-induced obese mice. PLoS One 2019; 14:e0205477. [PMID: 30889182 PMCID: PMC6424405 DOI: 10.1371/journal.pone.0205477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 02/18/2019] [Indexed: 01/21/2023] Open
Abstract
Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.
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Rao X, Zhao S, Braunstein Z, Mao H, Razavi M, Duan L, Wei Y, Toomey AC, Rajagopalan S, Zhong J. Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways. EBioMedicine 2019; 41:50-61. [PMID: 30738832 PMCID: PMC6441950 DOI: 10.1016/j.ebiom.2019.01.065] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/31/2019] [Accepted: 01/31/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages. METHODS Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit. FINDINGS Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI < 30) patients. Oxidized low-density lipoprotein (oxLDL), but not native LDL, up-regulated DPP4 expression on macrophages with a preferential increase in CD36+ cells. OxLDL mediated DPP4 up-regulation was considerably diminished by Toll-like receptor-4 (TLR4) knockdown and CD36 deficiency. TRIF deficiency, but not MyD88 deficiency, attenuated oxLDL-induced DPP4 increase. INTERPRETATION Our study suggests a key role for oxLDL and downstream CD36/TLR4/TRIF in regulating DPP4 expression. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism linking post-prandial glucose metabolism to lipoprotein abnormality-potentiated atherosclerosis.
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Affiliation(s)
- Xiaoquan Rao
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA; Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA
| | - Shi Zhao
- Department of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Zachary Braunstein
- Department of Internal Medicine, Wexnel Medical Center, The Ohio State University, Columbus, OH, USA
| | - Hong Mao
- Department of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Michael Razavi
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA
| | - Lihua Duan
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA
| | - Yingying Wei
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA
| | - Amelia C Toomey
- Department of Health Sciences, University of Missouri, Columbia, MO, USA
| | - Sanjay Rajagopalan
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA
| | - Jixin Zhong
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA.
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M2 Macrophages as a Potential Target for Antiatherosclerosis Treatment. Neural Plast 2019; 2019:6724903. [PMID: 30923552 PMCID: PMC6409015 DOI: 10.1155/2019/6724903] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/06/2018] [Accepted: 11/28/2018] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic progressive inflammation course, which could induce life-threatening diseases such as stroke and myocardial infarction. Optimal medical treatments for atherosclerotic risk factors with current antihypertensive and lipid-lowering drugs (for example, statins) are widely used in clinical practice. However, many patients with established disease still continue to have recurrent cardiovascular events in spite of treatment with a state-of-the-art therapy. Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Hence, current treatment of atherosclerosis is still far from being satisfactory. Recently, M2 macrophages have been found associated with atherosclerosis regression. The M2 phenotype can secrete anti-inflammatory factors such as IL-10 and TGF-β, promote tissue remodeling and repairing through collagen formation, and clear dying cells and debris by efferocytosis. Therefore, modulators targeting macrophages' polarization to the M2 phenotype could be another promising treatment strategy for atherosclerosis. Two main signaling pathways, the Akt/mTORC/LXR pathway and the JAK/STAT6 pathway, are found playing important roles in M2 polarization. In addition, researchers have reported several potential approaches to modulate M2 polarization. Inhibiting or activating some kinds of enzymes, affecting transcription factors, or acting on several membrane receptors could regulate the polarization of the M2 phenotype. Besides, biomolecules, for example vitamin D, were found to affect the process of M2 polarization. Pomegranate juice could promote M2 polarization via unclear mechanism. In this review, we will discuss how M2 macrophages affect atherosclerosis regression, signal transduction in M2 polarization, and outline potential targets and compounds that affect M2 polarization, thus controlling the progress of atherosclerosis.
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Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. ACTA ACUST UNITED AC 2019; 27:341-360. [PMID: 30674032 DOI: 10.1007/s40199-019-00238-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Despite advances in our understanding of metabolic syndrome (MetS) and the treatment of each of its components separately, currently there is no single therapy approved to manage it as a single condition. Since multi-drug treatment increases drug interactions, decreases patient compliance and increases health costs, it is important to introduce single therapies that improve all of the MetS components. EVIDENCE ACQUISITION We conducted a PubMed, Scopus, Google Scholar, Web of Science, US FDA, utdo.ir and clinicaltrial.gov search, gathered the most relevant preclinical and clinical studies that have been published since 2010, and discussed the beneficial effects of dipeptidyl peptidase (DPP)-4 inhibitors to prevent and treat different constituent of the MetS as a single therapy. Furthermore, the pharmacology of DPP-4 inhibitors, focusing on pharmacodynamics, pharmacokinetics, drug interactions and their side effects are also reviewed. RESULTS DPP-4 inhibitors or gliptins are a new class of oral anti-diabetic drugs that seem safe drugs with no severe side effects, commonly GI disturbance, infection and inflammatory bowel disease. They increase mass and function of pancreatic β-cells, and insulin sensitivity in liver, muscle and adipose tissue. It has been noted that gliptin therapy decreases dyslipidemia. DPP-4 inhibitors increase fatty oxidation, and cholesterol efflux, and decrease hepatic triglyceride synthase and de novo lipogenesis. They delay gastric emptying time and lead to satiety. Besides, gliptin therapy has anti-inflammatory and anti-atherogenic impacts, and improves endothelial function and reduces vascular stiffness. CONCLUSION The gathered data prove the efficacy of DPP-4 inhibitors in managing MetS in some levels beyond anti-diabetic effects. This review could be a lead for designing new DPP-4 inhibitors with greatest effects on MetS in future. Introducing drugs with polypharmacologic effects could increase the patient's compliance and decrease the health cost that there is not in multi-drug therapy. Graphical abstract ᅟ.
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Affiliation(s)
- Maryam Rameshrad
- Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Mayfield House, Falmer, Brighton, West Sussex, BN1 9PH, UK
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Harnessing CXCL12 signaling to protect and preserve functional β-cell mass and for cell replacement in type 1 diabetes. Pharmacol Ther 2019; 193:63-74. [DOI: 10.1016/j.pharmthera.2018.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Chen CY, Wu VC, Lin CJ, Lin CS, Pan CF, Chen HH, Lin YF, Huang TM, Chen L, Wu CJ. Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors. Mayo Clin Proc 2018; 93:1760-1774. [PMID: 30343892 PMCID: PMC7126857 DOI: 10.1016/j.mayocp.2018.06.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 06/03/2018] [Accepted: 06/05/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long-term effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. PATIENTS AND METHODS Data from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis-requiring AKI were identified. Cox proportional hazards models and inverse-weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end-stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure. RESULTS Of a total of 6165 patients with diabetes weaning from dialysis-requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70-0.94; P=.04) and all-cause mortality (hazard ratio, 0.28; 95% CI, 0.23-0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups. CONCLUSION Dipeptidyl peptidase-4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis-requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.
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Key Words
- aki, acute kidney injury
- aki-d, dialysis-requiring acute kidney injury
- ckd, chronic kidney disease
- dm, diabetes mellitus
- dpp4, dipeptidyl peptidase-4
- dpp4i, dipeptidyl peptidase-4 inhibitior
- esrd, end-stage renal disease
- hhf, hospitalized heart failure
- hr, hazard ratio
- icd-9-cm, international classification of diseases, ninth revision, clinical modification
- iptw, inverse probability of treatment weighting
- kim-1, kidney injury molecule-1
- mace, major adverse cardiovascular event
- mi, myocardial infarction
- mpr, medication possession ratio
- nhi, national health insurance
- nhird, national health insurance research database
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Affiliation(s)
- Cheng-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Hsinchu, Taiwan; Department of Medicine, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Jui Lin
- Department of Medicine, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; Medicine, Mackay Medical College, Taipei, Taiwan
| | - Chih-Sheng Lin
- Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
| | - Chi-Feng Pan
- Department of Medicine, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Han-Hsiang Chen
- Department of Medicine, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Yu-Feng Lin
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tao-Min Huang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Likwang Chen
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Chih-Jen Wu
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; Medicine, Mackay Medical College, Taipei, Taiwan; Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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Is there a Chance to Promote Arteriogenesis by DPP4 Inhibitors Even in Type 2 Diabetes? A Critical Review. Cells 2018; 7:cells7100181. [PMID: 30360455 PMCID: PMC6210696 DOI: 10.3390/cells7100181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/08/2018] [Accepted: 10/18/2018] [Indexed: 12/18/2022] Open
Abstract
Cardiovascular diseases (CVD) are still the prevailing cause of death not only in industrialized countries, but even worldwide. Type 2 diabetes mellitus (type 2 DM) and hyperlipidemia, a metabolic disorder that is often associated with diabetes, are major risk factors for developing CVD. Recently, clinical trials proved the safety of gliptins in treating patients with type 2 DM. Gliptins are dipeptidyl-peptidase 4 (DPP4/CD26) inhibitors, which stabilize glucagon-like peptide-1 (GLP-1), thereby increasing the bioavailability of insulin. Moreover, blocking DPP4 results in increased levels of stromal cell derived factor 1 (SDF-1). SDF-1 has been shown in pre-clinical animal studies to improve heart function and survival after myocardial infarction, and to promote arteriogenesis, the growth of natural bypasses, compensating for the function of an occluded artery. Clinical trials, however, failed to demonstrate a superiority of gliptins compared to placebo treated type 2 DM patients in terms of cardiovascular (CV) outcomes. This review highlights the function of DPP4 inhibitors in type 2 DM, and in treating cardiovascular diseases, with special emphasis on arteriogenesis. It critically addresses the potency of currently available gliptins and gives rise to hope by pointing out the most relevant questions that need to be resolved.
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Wiciński M, Wódkiewicz E, Słupski M, Walczak M, Socha M, Malinowski B, Pawlak-Osińska K. Neuroprotective Activity of Sitagliptin via Reduction of Neuroinflammation beyond the Incretin Effect: Focus on Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6091014. [PMID: 30186862 PMCID: PMC6116461 DOI: 10.1155/2018/6091014] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 06/22/2018] [Accepted: 07/26/2018] [Indexed: 12/25/2022]
Abstract
Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), IL-17 (interleukin-17), and CD-163 (cluster of differentiation 163), and contributed to an increase in levels of anti-inflammatory factors: IL-10 (interleukin-10) and TGF-β (transforming growth factor β). Moreover, sitagliptin demonstrated antioxidative and antiapoptotic properties by modifying glutamate and glutathione levels within the region of hippocampus in mice. It has been observed that sitagliptin decreases accumulation of β-amyloid within encephalon structures in experimental models of Alzheimer's dementia. This effect may be connected with SDF-1α (stromal cell-derived factor 1α) concentration. Administration of sitagliptin caused a significant improvement in MMSE (Mini-Mental State Examination) tests used for assessment of dementias. The paper presents potential mechanisms of sitagliptin activity in conditions connected with neuroinflammation with special emphasis on Alzheimer's disease.
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Affiliation(s)
- Michał Wiciński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Eryk Wódkiewicz
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Słupski
- Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Walczak
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Socha
- Department of Obstetrics, Gynecology and Gynecological Oncology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Ujejskiego 75, 85-168 Bydgoszcz, Poland
| | - Bartosz Malinowski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Katarzyna Pawlak-Osińska
- Department of Pathophysiology of Hearing and Balance System, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
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Zhou Y, Guo Z, Yan W, Wang W. Cardiovascular effects of sitagliptin - An anti-diabetes medicine. Clin Exp Pharmacol Physiol 2018; 45:628-635. [DOI: 10.1111/1440-1681.12953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 04/03/2018] [Accepted: 04/12/2018] [Indexed: 01/28/2023]
Affiliation(s)
- Yi Zhou
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - Zhiying Guo
- Department of Pathophysiology; School of Basic Medicine; Jining Medical University; Shandong China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases; Beijing China
| | - Wenjing Yan
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - Wen Wang
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases; Beijing China
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Remm F, Kränkel N, Lener D, Drucker DJ, Sopper S, Brenner C. Sitagliptin Accelerates Endothelial Regeneration after Vascular Injury Independent from GLP1 Receptor Signaling. Stem Cells Int 2018; 2018:5284963. [PMID: 29531541 PMCID: PMC5822806 DOI: 10.1155/2018/5284963] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 11/23/2017] [Accepted: 12/02/2017] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION DPP4 inhibitors (gliptins) are commonly used antidiabetic drugs for the treatment of type 2 diabetes. Gliptins also act in a glucose-independent manner and show vasoregenerative effects. We have shown that gliptins can remarkably accelerate vascular healing after vascular injury. However, the underlying mechanisms remain unclear. Here, we examined potential signaling pathways linking gliptins to enhanced endothelial regeneration. METHODS AND RESULTS We used wild-type and GLP1 receptor knockout (Glp1r-/-) mice to investigate the underlying mechanisms of gliptin-induced reendothelialization. The prototype DPP4 inhibitor sitagliptin accelerated endothelial healing in both animal models. Improved endothelial growth was associated with gliptin-mediated progenitor cell recruitment into the diseased vascular wall via the SDF1-CXCR4 axis independent of GLP1R-dependent signaling pathways. Furthermore, SDF1 showed direct proproliferative effects on endothelial cells. Excessive neointimal formation was not observed in gliptin- or placebo-treated Glp1r-/- mice. CONCLUSION We identified the SDF1-CXCR4 axis as a crucial signaling pathway for endothelial regeneration after acute vascular injury. Furthermore, SDF1 can directly increase endothelial cell proliferation. Gliptin-mediated potentiation of endothelial regeneration was preserved in Glp1r-/- animals. Thus, gliptin-mediated endothelial regeneration proceeds through SDF-1/CXCR4 in a GLP1R-independent manner after acute vascular injury.
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Affiliation(s)
- Friederike Remm
- Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicolle Kränkel
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Daniela Lener
- Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniel J. Drucker
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Sieghart Sopper
- Department of Internal Medicine V, Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Brenner
- Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Cardiology, Reha Zentrum Muenster, Münster, Tirol, Austria
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Dingenouts CKE, Bakker W, Lodder K, Wiesmeijer KC, Moerkamp AT, Maring JA, Arthur HM, Smits AM, Goumans MJ. Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction. PLoS One 2017; 12:e0189805. [PMID: 29253907 PMCID: PMC5734765 DOI: 10.1371/journal.pone.0189805] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 12/02/2017] [Indexed: 12/11/2022] Open
Abstract
AIMS Hereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFβ co-receptor endoglin. Dysfunctional homing of HHT1 mononuclear cells (MNCs) towards the infarcted myocardium hampers cardiac recovery. HHT1-MNCs have elevated expression of dipeptidyl peptidase-4 (DPP4/CD26), which inhibits recruitment of CXCR4-expressing MNCs by inactivation of stromal cell-derived factor 1 (SDF1). We hypothesize that inhibiting DPP4 will restore homing of HHT1-MNCs to the infarcted heart and improve cardiac recovery. METHODS AND RESULTS After inducing myocardial infarction (MI), wild type (WT) and endoglin heterozygous (Eng+/-) mice were treated for 5 days with the DPP4 inhibitor Diprotin A (DipA). DipA increased the number of CXCR4+ MNCs residing in the infarcted Eng+/- hearts (Eng+/- 73.17±12.67 vs. Eng+/- treated 157.00±11.61, P = 0.0003) and significantly reduced infarct size (Eng+/- 46.60±9.33% vs. Eng+/- treated 27.02±3.04%, P = 0.03). Echocardiography demonstrated that DipA treatment slightly deteriorated heart function in Eng+/- mice. An increased number of capillaries (Eng+/- 61.63±1.43 vs. Eng+/- treated 74.30±1.74, P = 0.001) were detected in the infarct border zone whereas the number of arteries was reduced (Eng+/- 11.88±0.63 vs. Eng+/- treated 6.38±0.97, P = 0.003). Interestingly, while less M2 regenerative macrophages were present in Eng+/- hearts prior to DipA treatment, (WT 29.88±1.52% vs. Eng+/- 12.34±1.64%, P<0.0001), DPP4 inhibition restored the number of M2 macrophages to wild type levels. CONCLUSIONS In this study, we demonstrate that systemic DPP4 inhibition restores the impaired MNC homing in Eng+/- animals post-MI, and enhances cardiac repair, which might be explained by restoring the balance between the inflammatory and regenerative macrophages present in the heart.
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Affiliation(s)
| | - Wineke Bakker
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Kirsten Lodder
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Karien C. Wiesmeijer
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Asja T. Moerkamp
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Janita A. Maring
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Helen M. Arthur
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom
| | - Anke M. Smits
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Marie-José Goumans
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
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Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, Piegari E, Berrino L, Rossi F, De Angelis A, Urbanek K. Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. Br J Pharmacol 2017; 174:4070-4086. [PMID: 27922176 PMCID: PMC5659996 DOI: 10.1111/bph.13686] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 11/07/2016] [Accepted: 11/29/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE Heart failure with preserved ejection fraction (HFpEF) is a systemic syndrome driven by co-morbidities, and its pathophysiology is poorly understood. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure have prompted experimental and clinical investigations of DPP4 inhibitors in the cardiovascular system. Here we have investigated whether the DPP4 inhibitor sitagliptin affected the progression of HFpEF independently of its effects on glycaemia. EXPERIMENTAL APPROACH Seven-week-old Dahl salt-sensitive rats were fed a high-salt diet for 5 weeks to induce hypertension. Then the rats continued with the high-salt diet and were treated with either sitagliptin (10 mg·kg-1 ) or vehicle for the following 8 weeks. Blood pressure and cardiac function were measured in vivo. Histochemical and molecular biology analyses of myocardium were used to assay cytokines, fibrotic markers, DPP4 and glucagon-like peptide-1 (GLP-1)/GLP-1 receptor. KEY RESULTS Treatment with sitagliptin attenuated diastolic dysfunction, reduced mortality and reduced cardiac DPP4 activity, along with increased circulating GLP-1 and myocardial expression of GLP-1 receptors. Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) were reduced. Sitagliptin treatment decreased the levels of endothelial NOS monomer, responsible for generation of ROS, while the amount of NO-producing dimeric form increased. Markers of oxidative and nitrosative stress were decreased. Moreover, increased collagen deposition and activation of pro-fibrotic signalling, inducing elevated myocardial stiffness, were attenuated by sitagliptin treatment. CONCLUSIONS AND IMPLICATIONS Sitagliptin positively modulated active relaxation and passive diastolic compliance by decreasing inflammation-related endothelial dysfunction and fibrosis, associated with HFpEF. LINKED ARTICLES This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
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Affiliation(s)
- Grazia Esposito
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Donato Cappetta
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Rosa Russo
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Alessia Rivellino
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Loreta Pia Ciuffreda
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | | | - Elena Piegari
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Liberato Berrino
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Francesco Rossi
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Antonella De Angelis
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Konrad Urbanek
- Department of Experimental Medicine, Section of PharmacologyUnivesity of Campania “Luigi Vanvitelli”NaplesItaly
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Hyperglycemia in Stroke Impairs Polarization of Monocytes/Macrophages to a Protective Noninflammatory Cell Type. J Neurosci 2017; 36:9313-25. [PMID: 27605608 DOI: 10.1523/jneurosci.0473-16.2016] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 07/14/2016] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Hyperglycemia is common in patients with acute stroke, even in those without preexisting diabetes, and denotes a bad outcome. However, the mechanisms underlying the detrimental effects of hyperglycemia are largely unclear. In a mouse model of ischemic stroke, we found that hyperglycemia increased the infarct volume and decreased the number of protective noninflammatory monocytes/macrophages in the ischemic brain. Ablation of peripheral monocytes blocked the detrimental effect of hyperglycemia, suggesting that monocytes are required. In hyperglycemic mice, α-dicarbonyl glucose metabolites, the precursors for advanced glycation end products, were significantly elevated in plasma and ischemic brain tissue. The receptor of advanced glycation end products, AGER (previously known as RAGE), interfered with polarization of macrophages to a noninflammatory phenotype. When Ager was deleted, hyperglycemia did not aggravate ischemic brain damage any longer. Independently of AGER, methylglyoxal reduced the release of endothelial CSF-1 (M-CSF), which stimulates polarization of macrophages to a noninflammatory phenotype in the microenvironment of the ischemic brain. In summary, our study identified α-dicarbonyls and AGER as mediators by which hyperglycemia lowers the number of protective noninflammatory macrophages and consequently increases ischemic brain damage. Modulating the metabolism of α-dicarbonyls or blocking AGER may improve the treatment of stroke patients with hyperglycemia. SIGNIFICANCE STATEMENT Although glucose is the main energy substrate of the brain, hyperglycemia aggravates ischemic brain damage in acute stroke. So far, clinical trials have indicated that insulin treatment provides no solution to this common clinical problem. This study shows, in an experimental stroke model, that hyperglycemia interferes with the polarization of monocytes/macrophages to a protective cell type. Key players are α-dicarbonyls and the receptor for advanced glycation end products (AGER). Deletion of AGER normalized monocyte/macrophage polarization and reversed the detrimental effects of hyperglycemia, suggesting new avenues to treat stroke patients.
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Shafiq M, Kong D, Kim SH. SDF-1α peptide tethered polyester facilitates tissue repair by endogenous cell mobilization and recruitment. J Biomed Mater Res A 2017; 105:2670-2684. [DOI: 10.1002/jbm.a.36130] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/30/2017] [Accepted: 05/15/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Muhammad Shafiq
- Korea University of Science and Technology; 176 Gajeong-dong Yuseong-gu Daejeon Republic of Korea
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology; Cheongryang Seoul 130-650 Republic of Korea
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Life Science; Nankai University; Tianjin 300071 China
| | - Deling Kong
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Life Science; Nankai University; Tianjin 300071 China
- Tianjin Key Laboratory of Biomedical Materials; Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical; Tianjin China
| | - Soo Hyun Kim
- Korea University of Science and Technology; 176 Gajeong-dong Yuseong-gu Daejeon Republic of Korea
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology; Cheongryang Seoul 130-650 Republic of Korea
- Department of Nano-Bio-Information Technology (NBIT), KU-KIST Graduate School of Converging Science and Technology; Korea University; Seoul 136-701 Republic of Korea
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Duan L, Rao X, Xia C, Rajagopalan S, Zhong J. The regulatory role of DPP4 in atherosclerotic disease. Cardiovasc Diabetol 2017; 16:76. [PMID: 28619058 PMCID: PMC5472996 DOI: 10.1186/s12933-017-0558-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 06/02/2017] [Indexed: 02/07/2023] Open
Abstract
The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4-incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis.
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Affiliation(s)
- Lihua Duan
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003 Fujian China
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH 44106 USA
| | - Xiaoquan Rao
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH 44106 USA
| | - Chang Xia
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH 44106 USA
- Department of Microbiology and Immunology, Wuhan Polytechnic University, Wuhan, 430023 Hubei China
| | - Sanjay Rajagopalan
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH 44106 USA
| | - Jixin Zhong
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH 44106 USA
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Delgado-Maroto V, Benitez R, Forte-Lago I, Morell M, Maganto-Garcia E, Souza-Moreira L, O’Valle F, Duran-Prado M, Lichtman AH, Gonzalez-Rey E, Delgado M. Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells. Sci Rep 2017; 7:46444. [PMID: 28406244 PMCID: PMC5390288 DOI: 10.1038/srep46444] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 03/17/2017] [Indexed: 12/16/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases. Its role in inflammatory cardiovascular disorders is largely unexplored. The aim of this study is to investigate the potential therapeutic effects of cortistatin in two well-established preclinical models of atherosclerosis, and the molecular and cellular mechanisms involved. Systemic treatment with cortistatin reduced the number and size of atherosclerotic plaques in carotid artery, heart, aortic arch and aorta in acute and chronic atherosclerosis induced in apolipoprotein E-deficient mice fed a high-lipid diet. This effect was exerted at multiple levels. Cortistatin reduced Th1/Th17-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and lymphoid organs. Moreover, cortistatin reduced the capacity of endothelial cells to bind and recruit immune cells to the plaque and impaired the formation of foam cells by enhancing cholesterol efflux from macrophages. Cortistatin emerges as a new candidate for the treatment of the clinical manifestations of atherosclerosis.
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Affiliation(s)
| | - Raquel Benitez
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
| | - Irene Forte-Lago
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
| | - Maria Morell
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
| | - Elena Maganto-Garcia
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
| | | | - Francisco O’Valle
- Department of Pathology, School of Medicine, University of Granada, Granada, Spain
| | - Mario Duran-Prado
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Medical Sciences, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Andrew H. Lichtman
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
| | - Elena Gonzalez-Rey
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
| | - Mario Delgado
- Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
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Dei Cas A, Spigoni V, Cito M, Aldigeri R, Ridolfi V, Marchesi E, Marina M, Derlindati E, Aloe R, Bonadonna RC, Zavaroni I. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes. Cardiovasc Diabetol 2017; 16:27. [PMID: 28231835 PMCID: PMC5324295 DOI: 10.1186/s12933-017-0503-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 02/03/2017] [Indexed: 12/19/2022] Open
Abstract
Background Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown. Methods Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34+/CD133+/KDR+/106 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed. Results Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p < 0.0001) improved glucose control. At 12 months, V significantly increased EPC number (p < 0.05) and significantly reduced (C-term) SDF-1α plasma levels (p < 0.01) compared to G, with no differences in inflammatory biomarkers. Conclusions V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013
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Affiliation(s)
- Alessandra Dei Cas
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy. .,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
| | - Valentina Spigoni
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Monia Cito
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Raffaella Aldigeri
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | | | | | - Michela Marina
- Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Eleonora Derlindati
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Rosalia Aloe
- Biochemistry, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Riccardo C Bonadonna
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy.,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Ivana Zavaroni
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy.,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
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Zhong J, Kankanala S, Rajagopalan S. Dipeptidyl peptidase-4 inhibition: insights from the bench and recent clinical studies. Curr Opin Lipidol 2016; 27:484-492. [PMID: 27472408 PMCID: PMC5147592 DOI: 10.1097/mol.0000000000000340] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Atherosclerosis is the leading cause of death globally. The pathophysiology of atherosclerosis is not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. Recent advances in the understanding of DPP4 function in atherosclerosis will be discussed in this review. RECENT FINDINGS Multiple preclinical and clinical studies suggest DPP4/glucagon-like peptide-1 axis is involved in the development of atherosclerotic disease. However, several recent trials assessing the cardiovascular effects of DPP4 inhibition indicate enzymatic inhibition of DPP4 lacks beneficial effects on cardiovascular disease. SUMMARY Catalytic inhibition of DPP4 with DPP4 inhibitors alters pathways that could favor cardioprotection. Glucagon-like peptide-1 receptor-independent aspects of DPP4 function may contribute to the overall neutral effects on cardiovascular outcome seen in the outcome trials.
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Affiliation(s)
- Jixin Zhong
- Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA *Jixin Zhong and Sanjay Rajagopalan contributed equally to the writing of this article
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