|
1
|
Li Q, Fu J, Park K, Shah H, Li Q, Wu IH, King GL. Insulin receptors in vascular smooth muscle cells regulate plaque stability of atherosclerosis. Cardiovasc Res 2024; 120:2017-2030. [PMID: 39197028 PMCID: PMC11646105 DOI: 10.1093/cvr/cvae193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/09/2024] [Accepted: 07/05/2024] [Indexed: 08/30/2024] Open
Abstract
AIMS Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with an elevated risk of unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability, as deleting insulin receptors (IRs) in VSMCs decreases their proliferation and enhances apoptosis. METHODS AND RESULTS Direct effects of insulin on VSMCs to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMCs with SMIRKO/ApoE-/-, Myh11-CreERT2EYFP+/ApoE-/-, and Myh11-CreERT2EYFP+IRKO/ApoE-/- mice, which were also used for lineage tracing studies. Compared with ApoE-/- mice, SMIRKO/ApoE-/- mice exhibited more atherosclerotic plaques, which contained less VSMCs and collagen but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory, which increased in the aortas of Myh11-CreERT2EYFP+IRKO/ApoE-/- mice compared with control mice. Isolated VSMCs lacking IRs expressed higher inflammatory cytokines than cells with IRs. Cell-based studies indicated that insulin's anti-apoptotic and pro-proliferative effects in VSMCs were mediated via activation of the IR/Akt pathway, which were decreased in VSMCs from SMIRKO or high-fat diet mice. An analysis of the IR targets that regulated inflammatory cytokines in VSMCs showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with a loss of IRs. Insulin inhibited Thbs1 expression, but not Mmp2 expression, through p-Akt/p-FoxO1 pathways in VSMCs from ApoE-/- mice, and was impaired in cells from SMIRKO/ApoE-/- mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMCs. CONCLUSION Insulin via IRs has significant actions in VSMCs to decrease inflammation, apoptosis, and ECM turnover via the activation of Akt and FoxO1 pathways. The inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques.
Collapse
MESH Headings
- Animals
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Plaque, Atherosclerotic
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Atherosclerosis/pathology
- Atherosclerosis/metabolism
- Atherosclerosis/genetics
- Apoptosis
- Mice, Knockout, ApoE
- Disease Models, Animal
- Signal Transduction
- Receptor, Insulin/metabolism
- Receptor, Insulin/genetics
- Aortic Diseases/pathology
- Aortic Diseases/metabolism
- Aortic Diseases/genetics
- Aortic Diseases/prevention & control
- Mice, Inbred C57BL
- Cell Proliferation
- Insulin/metabolism
- Male
- Cells, Cultured
- Rupture, Spontaneous
- Insulin Resistance
- Proto-Oncogene Proteins c-akt/metabolism
- Thrombospondin 1/metabolism
- Thrombospondin 1/genetics
- Aorta/pathology
- Aorta/metabolism
- Matrix Metalloproteinase 2/metabolism
- Matrix Metalloproteinase 2/genetics
- Inflammation Mediators/metabolism
- Necrosis
- Apolipoproteins E/genetics
- Apolipoproteins E/deficiency
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Mice
- Receptor, IGF Type 1
Collapse
Affiliation(s)
- Qian Li
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - Jialin Fu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - Kyoungmin Park
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - Hetal Shah
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - Qin Li
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - I Hsien Wu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| | - George L King
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
| |
Collapse
|
|
2
|
Gonzalez-Sanchez FA, Sanchez-Huerta TM, Huerta-Gonzalez A, Sepulveda-Villegas M, Altamirano J, Aguilar-Aleman JP, Garcia-Varela R. Diabetes current and future translatable therapies. Endocrine 2024; 86:865-881. [PMID: 38971945 DOI: 10.1007/s12020-024-03944-8] [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: 04/19/2024] [Accepted: 06/23/2024] [Indexed: 07/08/2024]
Abstract
Diabetes is one of the major diseases and concerns of public health systems that affects over 200 million patients worldwide. It is estimated that 90% of these patients suffer from diabetes type 2, while 10% present diabetes type 1. This type of diabetes and certain types of diabetes type 2, are characterized by dysregulation of blood glycemic levels due to the total or partial depletion of insulin-secreting pancreatic β-cells. Different approaches have been proposed for long-term treatment of insulin-dependent patients; amongst them, cell-based approaches have been the subject of basic and clinical research since they allow blood glucose level sensing and in situ insulin secretion. The current gold standard for insulin-dependent patients is on-demand exogenous insulin application; cell-based therapies aim to remove this burden from the patient and caregivers. In recent years, protocols to isolate and implant pancreatic islets from diseased donors have been developed and tested in clinical trials. Nevertheless, the shortage of donors, along with the need of immunosuppressive companion therapies, have pushed researchers to focus their attention and efforts to overcome these disadvantages and develop alternative strategies. This review discusses current tested clinical approaches and future potential alternatives for diabetes type 1, and some diabetes type 2, insulin-dependent patients. Additionally, advantages and disadvantages of these discussed methods.
Collapse
Affiliation(s)
- Fabio Antonio Gonzalez-Sanchez
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Triana Mayra Sanchez-Huerta
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Alexandra Huerta-Gonzalez
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Maricruz Sepulveda-Villegas
- Departamento de Medicina Genómica y Hepatología, Hospital Civil de Guadalajara, "Fray Antonio Alcalde", Guadalajara, 44280, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44100, Jalisco, Mexico
| | - Julio Altamirano
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Epigmenio González 500, San Pablo, 76130, Santiago de Queretaro, Qro, México
| | - Juan Pablo Aguilar-Aleman
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Ingenieria Biomedica, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Rebeca Garcia-Varela
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México.
- Carbone Cancer Center, University of Wisconsin - Madison, 1111 Highland Ave, Wisconsin, 53705, Madison, USA.
| |
Collapse
|
|
3
|
Ajay AK, Zhu LJ, Zhao L, Liu Q, Ding Y, Chang YC, Shah SI, Hsiao LL. Local vascular Klotho mediates diabetes-induced atherosclerosis via ERK1/2 and PI3-kinase-dependent signaling pathways. Atherosclerosis 2024; 396:118531. [PMID: 38996716 DOI: 10.1016/j.atherosclerosis.2024.118531] [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: 12/06/2022] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND AND AIMS Diabetes is one of the major causes of cardiovascular disease (CVD). As high as 29 % of patients with diabetes develop atherosclerosis. Vascular Smooth Muscle Cells (VSMCs) are a key mediator in the pathogenesis of atherosclerosis, generating pro-inflammatory and proliferative characteristics in atherosclerotic lesions. METHODS We used human atherosclerotic samples, developed diabetes-induced atherosclerotic mice, and generated loss of function and gain of function in Klotho human aortic smooth muscle cells to investigate the function of Klotho in atherosclerosis. RESULTS We found that Klotho expression is decreased in smooth muscle actin-positive cells in patients with diabetes and atherosclerosis. Consistent with human data, we found that Apoe knockout mice with streptozotocin-induced diabetes fed on a high-fat diet showed decreased expression of Klotho in SMCs. Additionally, these mice showed increased expression of TGF-β, MMP9, phosphorylation of ERK and Akt. Further, we utilized primary Human Aortic Smooth Muscle Cells (HASMCs) with d-glucose under dose-response and in time-dependent conditions to study the role of Klotho in these cells. Klotho gain of function and loss of function studies showed that Klotho inversely regulated the expression of atherosclerotic markers TGF-β, MMP2, MMP9, and Fractalkine. Further, High Glucose (HG) induced Akt, and ERK1/2 phosphorylation were enhanced or mitigated by endogenous Klotho deficiency or its overexpression respectively. PI3K/Akt and MAPK/ERK inhibition partially abolished the HG-induced upregulation of TGF-β, MMP2, MMP9, and Fractalkine. Additionally, Klotho knockdown increased the proliferation of HASMCs and enhanced α-SMA and TGF-β expression. CONCLUSIONS Taken together, these results indicate that local vascular Klotho is involved in diabetes-induced atherosclerosis, which is via PI3K/Akt and ERK1/2-dependent signaling pathways.
Collapse
MESH Headings
- Klotho Proteins/metabolism
- Animals
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Atherosclerosis/genetics
- Glucuronidase/metabolism
- Glucuronidase/genetics
- Humans
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/complications
- Mice, Knockout, ApoE
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Male
- Signal Transduction
- Cells, Cultured
- Aorta/pathology
- Aorta/metabolism
- MAP Kinase Signaling System
- Mice
- Aortic Diseases/pathology
- Aortic Diseases/metabolism
- Aortic Diseases/genetics
- Aortic Diseases/enzymology
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/metabolism
- Phosphatidylinositol 3-Kinases/metabolism
- Mice, Inbred C57BL
- Proto-Oncogene Proteins c-akt/metabolism
- Cell Proliferation
Collapse
Affiliation(s)
- Amrendra K Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115.
| | - Lang-Jing Zhu
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115; Department of Nephrology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Li Zhao
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115; Division of Renal Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Qinghua Liu
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115; Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yan Ding
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115
| | - Yu-Chun Chang
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115
| | - Sujal I Shah
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115
| | - Li-Li Hsiao
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 02115.
| |
Collapse
|
|
4
|
Yang J, Gourley GR, Gilbertsen A, Chen C, Wang L, Smith K, Namenwirth M, Yang L. High Glucose Levels Promote Switch to Synthetic Vascular Smooth Muscle Cells via Lactate/GPR81. Cells 2024; 13:236. [PMID: 38334628 PMCID: PMC10854508 DOI: 10.3390/cells13030236] [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: 11/28/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/10/2024] Open
Abstract
Hyperglycemia, lipotoxicity, and insulin resistance are known to increase the secretion of extracellular matrix from cardiac fibroblasts as well as the activation of paracrine signaling from cardiomyocytes, immune cells, and vascular cells, which release fibroblast-activating mediators. However, their influences on vascular smooth muscle cells (vSMCs) have not been well examined. This study aimed to investigate whether contractile vascular vSMCs could develop a more synthetic phenotype in response to hyperglycemia. The results showed that contractile and synthetic vSMCs consumed high glucose in different ways. Lactate/GPR81 promotes the synthetic phenotype in vSMCs in response to high glucose levels. The stimulation of high glucose was associated with a significant increase in fibroblast-like features: synthetic vSMC marker expression, collagen 1 production, proliferation, and migration. GPR81 expression is higher in blood vessels in diabetic patients and in the high-glucose, high-lipid diet mouse. The results demonstrate that vSMCs assume a more synthetic phenotype when cultured in the presence of high glucose and, consequently, that the high glucose could trigger a vSMC-dependent cardiovascular disease mechanism in diabetes via lactate/GPR81.
Collapse
Affiliation(s)
- Jing Yang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, China
- Institute of Virology, Hubei University of Medicine, Shiyan 442000, China
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Glenn R. Gourley
- Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; (G.R.G.); (M.N.)
| | - Adam Gilbertsen
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (A.G.); (K.S.)
| | - Chi Chen
- Department of Food Science and Nutrition, CFANS, University of Minnesota, St Paul, MN 55108, USA; (C.C.); (L.W.)
| | - Lei Wang
- Department of Food Science and Nutrition, CFANS, University of Minnesota, St Paul, MN 55108, USA; (C.C.); (L.W.)
| | - Karen Smith
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (A.G.); (K.S.)
| | - Marion Namenwirth
- Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; (G.R.G.); (M.N.)
| | - Libang Yang
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (A.G.); (K.S.)
| |
Collapse
|
|
5
|
Koval OM, Nguyen EK, Mittauer DJ, Ait-Aissa K, Chinchankar WC, Grumbach IM. Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes. Int J Mol Sci 2023; 24:12897. [PMID: 37629079 PMCID: PMC10454141 DOI: 10.3390/ijms241612897] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.
Collapse
Affiliation(s)
- Olha M. Koval
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Emily K. Nguyen
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Dylan J. Mittauer
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Karima Ait-Aissa
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - William C. Chinchankar
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Isabella M. Grumbach
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Veterans Affairs Healthcare System, Iowa City, IA 52246, USA
| |
Collapse
|
|
6
|
Sobolevskaya EV, Shumkov OA, Smagin MA, Guskov AE, Malysheva AV, Atuchin VV, Nimaev VV. Markers of Restenosis after Percutaneous Transluminal Balloon Angioplasty in Patients with Critical Limb Ischemia. Int J Mol Sci 2023; 24:ijms24109096. [PMID: 37240440 DOI: 10.3390/ijms24109096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/14/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form is chronic ischemia, characterized by pain at rest and ischemic ulcers, ultimately increasing the risk of limb loss and cardiovascular mortality. Therefore, patients with critical limb ischemia need limb revascularization. Percutaneous transluminal balloon angioplasty is one of the least invasive and safe approaches, with advantages for patients with comorbidities. However, after this procedure, restenosis is still possible. Early detection of changes in the composition of some molecules as markers of restenosis will help screen patients at the risk of restenosis, as well as find ways to apply efforts for further directions of inhibition of this process. The purpose of this review is to provide the most important and up-to-date information on the mechanisms of restenosis development, as well as possible predictors of their occurrence. The information collected in this publication may be useful in predicting outcomes after surgical treatment and will also find new ways for the target implication to the mechanisms of development of restenosis and atherosclerosis.
Collapse
Affiliation(s)
- Elvira V Sobolevskaya
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Oleg A Shumkov
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Mikhail A Smagin
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Andrey E Guskov
- Laboratory of Scientometrics and Scientific Communications, Russian Research Institute of Economics, Politics and Law in Science and Technology, Moscow 127254, Russia
| | - Alexandra V Malysheva
- Laboratory of Scientometrics and Scientific Communications, Russian Research Institute of Economics, Politics and Law in Science and Technology, Moscow 127254, Russia
| | - Victor V Atuchin
- Laboratory of Optical Materials and Structures, Institute of Semiconductor Physics, SB RAS, Novosibirsk 630090, Russia
- Research and Development Department, Kemerovo State University, Kemerovo 650000, Russia
- Department of Industrial Machinery Design, Novosibirsk State Technical University, Novosibirsk 630073, Russia
- R&D Center "Advanced Electronic Technologies", Tomsk State University, Tomsk 634034, Russia
| | - Vadim V Nimaev
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| |
Collapse
|
|
7
|
Koval OM, Nguyen EK, Mittauer DJ, Ait-Aissa K, Chinchankar W, Qian L, Madesh M, Dai DF, Grumbach IM. The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.15.528765. [PMID: 36824758 PMCID: PMC9948984 DOI: 10.1101/2023.02.15.528765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Background Type 2 diabetes (T2D) is associated with a strongly increased risk for restenosis after angioplasty driven by proliferation of vascular smooth muscle cells (VSMCs). Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on ROS and intracellular [Ca 2+ ] that both drive cell proliferation, occur in T2D and are regulated by mitochondrial activity. Methods Using a diet-induced mouse model of T2D, the inhibition of the mitochondrial Ca 2+ /calmodulin-dependent kinase II (mtCaMKII), a regulator of Ca 2+ entry via the mitochondrial Ca 2+ uniporter selectively in VSMCs, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. Results In T2D, the inhibition of mtCaMKII reduced both neointima formation after mechanical injury and the proliferation of cultured VSMCs. VSMCs from T2D mice displayed accelerated proliferation, reduced mitochondrial Ca 2+ entry and membrane potential with elevated baseline [Ca 2+ ] cyto compared to cells from normoglycemic mice. Accelerated proliferation after PDGF treatment was driven by activation of Erk1/2 and its upstream regulators. Hyperactivation of Erk1/2 was Ca 2+ -dependent rather than mitochondrial ROS-driven Ca 2+ -dependent and included the activation of CaMKII in the cytosol. The inhibition of mtCaMKII exaggerated the Ca 2+ imbalance by lowering mitochondrial Ca 2+ entry and increasing baseline [Ca 2+ ] cyto , further enhancing baseline Erk1/2 activation. With inhibition of mtCaMKII, PDGF treatment had no additional effect on cell proliferation. Inhibition of activated CaMKII in the cytosol decreased excessive Erk1/2 activation and reduced VSMC proliferation. Conclusions Collectively, our results provide evidence for the molecular mechanisms of enhanced VSMC proliferation after mechanical injury by mitochondrial Ca 2+ entry in T2D.
Collapse
Affiliation(s)
- Olha M. Koval
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Emily K. Nguyen
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Dylan J. Mittauer
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Karima Ait-Aissa
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - William Chinchankar
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Lan Qian
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Muniswamy Madesh
- Center for Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Texas Health San Antonio, San Antonio, Texas 78229, USA
| | - Dao-Fu Dai
- Division of Pathology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Isabella M. Grumbach
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City IA 52242, USA
- Veterans Affairs Healthcare System, Iowa City, IA 52246, USA
| |
Collapse
|
|
8
|
Poniedziałek-Czajkowska E, Mierzyński R, Leszczyńska-Gorzelak B. Preeclampsia and Obesity-The Preventive Role of Exercise. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:1267. [PMID: 36674022 PMCID: PMC9859423 DOI: 10.3390/ijerph20021267] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 06/10/2023]
Abstract
Obesity is now recognized as a worldwide epidemic. An inadequate diet and reduced physical activity are acknowledged as the leading causes of excess body weight. Despite growing evidence that obesity is a risk factor for unsuccessful pregnancies, almost half of all women who become pregnant today are overweight or obese. Common complications of pregnancy in this group of women are preeclampsia and gestational hypertension. These conditions are also observed more frequently in women with excessive weight gain during pregnancy. Preeclampsia is one of the most serious pregnancy complications with an unpredictable course, which in its most severe forms, threatens the life and health of the mother and her baby. The early identification of the risk factors for preeclampsia development, including obesity, allows for the implementation of prophylaxis and a reduction in maternal and fetal complications risk. Additionally, preeclampsia and obesity are the recognized risk factors for developing cardiovascular disease in later life, so prophylaxis and treating obesity are paramount for their prevention. Thus, a proper diet and physical activity might play an essential role in the prophylaxis of preeclampsia in this group of women. Limiting weight gain during pregnancy and modifying the metabolic risk factors with regular physical exercise creates favorable metabolic conditions for pregnancy development and benefits the elements of the pathogenetic sequence for preeclampsia development. In addition, it is inexpensive, readily available and, in the absence of contraindications to its performance, safe for the mother and fetus. However, for this form of prevention to be effective, it should be applied early in pregnancy and, for overweight and obese women, proposed as an essential part of planning pregnancy. This paper aims to present the mechanisms of the development of hypertension in pregnancy in obese women and the importance of exercise in its prevention.
Collapse
|
|
9
|
Tikhonova IV, Grinevich AA, Tankanag AV, Safronova VG. Skin Microhemodynamics and Mechanisms of Its Regulation in Type 2 Diabetes Mellitus. Biophysics (Nagoya-shi) 2022; 67:647-659. [PMID: 36281313 PMCID: PMC9581453 DOI: 10.1134/s0006350922040200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 11/07/2022] Open
Abstract
The review presents modern ideas about peripheral microhemodynamics, approaches to the ana-lysis of skin blood flow oscillations and their diagnostic significance. Disorders of skin microhemodynamics in type 2 diabetes mellitus (DM) and the possibility of their interpretation from the standpoint of external and internal interactions between systems of skin blood flow regulation, based on a comparison of couplings in normal and pathological conditions, including models of pathologies on animals, are considered. The factors and mechanisms of vasomotor regulation, among them receptors and signaling events in endothelial and smooth muscle cells considered as models of microvessels are discussed. Attention was drawn to the disturbance of Ca2+-dependent regulation of coupling between vascular cells and NO-dependent regulation of vasodilation in diabetes mellitus. The main mechanisms of insulin resistance in type 2 DM are considered to be a defect in the number of insulin receptors and impaired signal transduction from the receptor to phosphatidylinositol-3-kinase and downstream targets. Reactive oxygen species plays an important role in vascular dysfunction in hyperglycemia. It is assumed that the considered molecular and cellular mechanisms of microhemodynamics regulation are involved in the formation of skin blood flow oscillations. Parameters of skin blood microcirculation can be used as diagnostic and prognostic markers for assessing the state of the body.
Collapse
Affiliation(s)
- I. V. Tikhonova
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow oblast Russia
| | - A. A. Grinevich
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow oblast Russia
| | - A. V. Tankanag
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow oblast Russia
| | - V. G. Safronova
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow oblast Russia
| |
Collapse
|
|
10
|
Ye J, Li L, Wang M, Ma Q, Tian Y, Zhang Q, Liu J, Li B, Zhang B, Liu H, Sun G. Diabetes Mellitus Promotes the Development of Atherosclerosis: The Role of NLRP3. Front Immunol 2022; 13:900254. [PMID: 35844498 PMCID: PMC9277049 DOI: 10.3389/fimmu.2022.900254] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/01/2022] [Indexed: 11/22/2022] Open
Abstract
Atherosclerosis is one of the main complications of diabetes mellitus, involving a variety of pathogenic factors. Endothelial dysfunction, inflammation, and oxidative stress are hallmarks of diabetes mellitus and atherosclerosis. Although the ability of diabetes to promote atherosclerosis has been demonstrated, a deeper understanding of the underlying biological mechanisms is critical to identifying new targets. NLRP3 plays an important role in both diabetes and atherosclerosis. While the diversity of its activation modes is one of the underlying causes of complex effects in the progression of diabetes and atherosclerosis, it also provides many new insights for targeted interventions in metabolic diseases.
Collapse
Affiliation(s)
- Jingxue Ye
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lanfang Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiuxiao Ma
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu Tian
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiong Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiushi Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bengang Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Guibo Sun, ; Haitao Liu,
| | - Guibo Sun
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Guibo Sun, ; Haitao Liu,
| |
Collapse
|
|
11
|
Markousis-Mavrogenis G, Bacopoulou F, Mavragani C, Voulgari P, Kolovou G, Kitas GD, Chrousos GP, Mavrogeni SI. Coronary microvascular disease: The "Meeting Point" of Cardiology, Rheumatology and Endocrinology. Eur J Clin Invest 2022; 52:e13737. [PMID: 34939183 DOI: 10.1111/eci.13737] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Exertional chest pain/dyspnea or chest pain at rest are the main symptoms of coronary artery disease (CAD), which are traditionally attributed to insufficiency of the epicardial coronary arteries. However, 2/3 of women and 1/3 of men with angina and 10% of patients with acute myocardial infarction have no evidence of epicardial coronary artery stenosis in X-ray coronary angiography. In these cases, coronary microvascular disease (CMD) is the main causative factor. AIMS To present the pathophysiology of CMD in Cardiology, Rheumatology and Endocrinology. MATERIALS-METHODS The pathophysiology of CMD in Cardiology, Rheumatology and Endocrinology was evaluated. It includes impaired microvascular vasodilatation, which leads to inability of the organism to deal with myocardial oxygen needs and, hence, development of ischemic pain. CMD, observed in inflammatory autoimmune rheumatic and endocrine/metabolic disorders, brings together Cardiology, Rheumatology and Endocrinology. Causative factors include persistent systemic inflammation and endocrine/metabolic abnormalities influencing directly the coronary microvasculature. In the past, the evaluation of microcirculation was feasible only with the use of invasive techniques, such as coronary flow reserve assessment. Currently, the application of advanced imaging modalities, such as cardiovascular magnetic resonance (CMR), can evaluate CMD non-invasively and without ionizing radiation. RESULTS CMD may present with a variety of symptoms with 1/3 to 2/3 of them expressed as typical chest pain in effort, more commonly found in women during menopause than in men. Atypical presentation includes chest pain at rest or exertional dyspnea,but post exercise symptoms are not uncommon. The treatment with nitrates is less effective in CMD, because their vasodilator action in coronary micro-circulation is less pronounced than in the epicardial coronary arteries. DISCUSSION Although both classic and new medications have been used in the treatment of CMD, there are still many questions regarding both the pathophysiology and the treatment of this disorder. The potential effects of anti-rheumatic and endocrine medications on the evolution of CMD need further evaluation. CONCLUSION CMD is a multifactorial disease leading to myocardial ischemia/fibrosis alone or in combination with epicardial coronary artery disease. Endothelial dysfunction/vasospasm, systemic inflammation, and/or neuroendocrine activation may act as causative factors and bring Cardiology, Rheumatology and Endocrinology together. Currently, the application of advanced imaging modalities, and specifically CMR, allows reliable assessment of the extent and severity of CMD. These measurements should not be limited to "pure cardiac patients", as it is known that CMD affects the majority of patients with autoimmune rheumatic and endocrine/metabolic disorders.
Collapse
Affiliation(s)
| | - Flora Bacopoulou
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Clio Mavragani
- Pathophysiology Department, University of Athens, Athens, Greece
| | | | - Genovefa Kolovou
- Onassis Cardiac Surgery Hospital, Athens, Greece.,Epidemiology Department, University of Manchester, Manchester, UK
| | - George D Kitas
- Epidemiology Department, University of Manchester, Manchester, UK
| | - George P Chrousos
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | | |
Collapse
|
|
12
|
Liu H, Ning F, Lash GE. Contribution of vascular smooth muscle cell apoptosis to spiral artery remodeling in early human pregnancy. Placenta 2022; 120:10-17. [DOI: 10.1016/j.placenta.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/02/2021] [Accepted: 02/07/2022] [Indexed: 11/15/2022]
|
|
13
|
Li B, Lei Z, Wu Y, Li B, Zhai M, Zhong Y, Ju P, Kou W, Shi Y, Zhang X, Peng W. The Association and Pathogenesis of SERPINA3 in Coronary Artery Disease. Front Cardiovasc Med 2021; 8:756889. [PMID: 34957248 PMCID: PMC8692672 DOI: 10.3389/fcvm.2021.756889] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Serine proteinase inhibitor A3 (SERPINA3) has been discovered in the pathogenesis of many human diseases, but little is known about the role of SERPINA3 in coronary artery disease (CAD). Therefore, we aim to determine its relationship with CAD and its function in the pathogenesis of atherosclerosis. Methods: In total 86 patients with CAD and 64 patients with non-CAD were compared. The plasma SERPINA3 levels were measured using ELISA. Logistic regression analysis and receiver-operating characteristic (ROC) analysis were performed to illustrate the association between plasma SERPINA3 levels and CAD. In vitro, real-time PCR (RT-PCR) and immunofluorescence staining were used to determine the expression of SERPINA3 in atherosclerotic plaques and their component cells. Then rat aortic smooth muscle cells (RASMCs) were transfected with siRNA to knock down the expression of SERPINA3 and human umbilical vein endothelial cells (HUVECs) were stimulated by SERPINA3 protein. EdU assay and scratch assay were used for assessing the capability of proliferation and migration. The cell signaling pathway was evaluated by western blot and RT-PCR. Results: Patients with CAD [104.4(54.5–259.2) μg/mL] had higher levels of plasma SERPINA3 than non-CAD [65.3(47.5–137.3) μg/mL] (P = 0.004). After being fully adjusted, both log-transformed and tertiles of plasma SERPINA3 levels were significantly associated with CAD. While its diagnostic value was relatively low since the area under the ROC curve was 0.64 (95% CI: 0.55–0.73). Secreted SERPINA3 might increase the expression of inflammatory factors in HUVECs. Vascular smooth muscle cells had the highest SERPINA3 expression among the aorta compared to endothelial cells and inflammatory cells. The knockdown of SERPINA3 in RASMCs attenuated its proliferation and migration. The phosphorylated IκBα and its downstream pathway were inhibited when SERPINA3 was knocked down. Conclusions: Elevated plasma SERPINA3 levels were associated with CAD. SERPINA3 can increase inflammatory factors expression in HUVECs. It can regulate VSMCs proliferation, migration, and releasing of inflammatory factors through the NF-κB signaling pathway. Thus, SERPINA3 played a significant role in the pathogenesis of atherosclerosis.
Collapse
Affiliation(s)
- Bo Li
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhijun Lei
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - You Wu
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bingyu Li
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ming Zhai
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuan Zhong
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Peinan Ju
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wenxin Kou
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yefei Shi
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xianling Zhang
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wenhui Peng
- Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| |
Collapse
|
|
14
|
Sagris M, Theofilis P, Antonopoulos AS, Oikonomou E, Paschaliori C, Galiatsatos N, Tsioufis K, Tousoulis D. Inflammation in Coronary Microvascular Dysfunction. Int J Mol Sci 2021; 22:ijms222413471. [PMID: 34948272 PMCID: PMC8703507 DOI: 10.3390/ijms222413471] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/05/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 μm, whose potential structural and functional abnormalities can lead to inappropriate dilatation and an inability to meet the required myocardium oxygen demands. This review focuses on the pathogenesis of coronary microvascular dysfunction and the capability of non-invasive screening methods to detect the phenomenon. Anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factor-alpha inhibitors, have been assessed recently and may constitute additional or alternative treatment approaches to reduce cardiovascular events in atherosclerotic heart disease characterized by coronary microvascular dysfunction.
Collapse
Affiliation(s)
- Marios Sagris
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
- Correspondence: ; Tel.:+30-213-2088099; Fax: +30-213-2088676
| | - Panagiotis Theofilis
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| | - Alexios S. Antonopoulos
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| | - Evangelos Oikonomou
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
- Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece
| | - Christina Paschaliori
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| | - Nikolaos Galiatsatos
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| | - Kostas Tsioufis
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| | - Dimitris Tousoulis
- Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (A.S.A.); (E.O.); (C.P.); (N.G.); (K.T.); (D.T.)
| |
Collapse
|
|
15
|
Oleic acid promotes atherosclerosis via multiple pathophysiological mechanisms. JOURNAL OF BIO-X RESEARCH 2021. [DOI: 10.1097/jbr.0000000000000117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
|
|
16
|
Handayani W, Suharjono, Yogiarto M. Analysis of HMGB-1 level before and after providing atorvastatin standard therapy in coronary artery disease patients with type-2 diabetes mellitus compared to without type-2 diabetes mellitus. J Basic Clin Physiol Pharmacol 2021; 32:439-446. [PMID: 34214372 DOI: 10.1515/jbcpp-2020-0442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/08/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Coronary artery disease (CAD) is one of the main causes of death from cardiovascular disease, because heart attacks result in atherosclerosis which causes narrowing of the arteries. Atorvastatin has a pleiotropic effect as anti-inflammatory through one of the target levels of High Mobility Group Box-1 (HMGB-1). This prospective observational study aimed to analyze the effect of atorvastatin on serum HMGB-1 levels in CAD. METHODS Samples were collected from prospective observation pre-post study in May-July 2018 with consecutive sampling method. Serum HMGB-1 levels were measured in patients with CAD who were given atorvastatin for CAD with type-2 diabetes mellitus compared without type-2 diabetes mellitus in a patient ward. Blood was collected on admission day and before the patient left the hospital. After centrifugation, serum samples were stored at -80 °C before measurement. We used an ELISA kit (IBL International) to determine HMGB-1 concentrations. This research protocol has been approved by the Ethical Committee of Dr. Soetomo General Hospital, Surabaya. RESULTS We enrolled 38 patients and divided them into two groups which 19 patients on CAD with type-2 diabetes mellitus and 19 patients without diabetes mellitus. Serum HMGB-1 levels in CAD with type-2 diabetes mellitus were increased significantly (p = 0.049) and not significantly decreased in CAD without type-2 diabetes mellitus (p = 0.480). The HMGB-1 level was not significantly different between the two groups (p = 0.210). CONCLUSIONS HMGB-1 levels after providing atorvastatin in CAD with type-2 diabetes mellitus increased significantly, meanwhile, in CAD without type-2 diabetes mellitus did not decrease significantly. The HMGB-1 level was not significantly different between the two groups. Longer time and more point for the collected sample needed for further research.
Collapse
Affiliation(s)
| | - Suharjono
- Department of Clinical Pharmacy, Faculty of Pharmacy,Universitas Airlangga, Surabaya, East Java, Indonesia
| | - Mohammad Yogiarto
- Cardiovascular, Department of Cardiology, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, Indonesia
| |
Collapse
|
|
17
|
Iacobini C, Vitale M, Pesce C, Pugliese G, Menini S. Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future. Antioxidants (Basel) 2021; 10:727. [PMID: 34063078 PMCID: PMC8147954 DOI: 10.3390/antiox10050727] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023] Open
Abstract
Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.
Collapse
Affiliation(s)
- Carla Iacobini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (C.I.); (M.V.); (S.M.)
| | - Martina Vitale
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (C.I.); (M.V.); (S.M.)
| | - Carlo Pesce
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy;
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (C.I.); (M.V.); (S.M.)
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (C.I.); (M.V.); (S.M.)
| |
Collapse
|
|
18
|
Duan H, Feng X, Huang X. Effects of insulin on the proliferation and global gene expression profile of A7r5 cells. Mol Biol Rep 2021; 48:1205-1215. [PMID: 33555531 DOI: 10.1007/s11033-021-06200-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/28/2021] [Indexed: 11/28/2022]
Abstract
Insulin contributes to atherosclerosis, but the potential mechanisms are kept unclear. In this study, insulin promoted proliferation of A7r5 cells. Microarray analysis indicated that insulin significantly changed 812 probe sets of genes, including 405 upregulated and 407 downregulated ones (fold change ≥ 1.5 or ≤ - 1.5; p < 0.05). Gene ontology analysis showed that the differentially expressed genes were involved in a number of processes, including the regulation of cell proliferation/migration/cycle, apoptotic process, oxidative stress, inflammatory response, mitogen-activated protein kinase (MAPK) activity, lipid metabolic process and extracellular matrix organization. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the genes were involved in biosynthesis of amino acids, fatty acid metabolism, glycolysis/gluconeogenesis, metabolic pathways, regulation of autophagy, cell cycle and apoptosis, as well as the PI3K-Akt, MAPK, mTOR and NF-κB signaling pathways. Additionally, insulin enhanced phosphorylation of MAPK kinase 1/2 and Akt, suggesting activation of the MAPK and PI3K-Akt signaling pathways. Inhibition of ERK1/2 reduced insulin-induced proliferation. This study revealed the proliferative effects of insulin and displayed global gene expression profile of A7r5 cells stimulated by insulin, suggesting new insight into the molecular pathogenesis of insulin promoting atherosclerosis.
Collapse
Affiliation(s)
- Huiming Duan
- Guangxi Key Laboratory of Chinese Medicine Foundation Research, Guangxi University of Chinese Medicine, Nanning, 530200, China.,Guangxi Scientific Experimental Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China
| | - Xiaotao Feng
- Guangxi Key Laboratory of Chinese Medicine Foundation Research, Guangxi University of Chinese Medicine, Nanning, 530200, China. .,Guangxi Scientific Experimental Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Xiaoqi Huang
- Laboratory of Medical Molecular Biology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, 530023, China
| |
Collapse
|
|
19
|
Lee MKS, Kraakman MJ, Dragoljevic D, Hanssen NMJ, Flynn MC, Al-Sharea A, Sreejit G, Bertuzzo-Veiga C, Cooney OD, Baig F, Morriss E, Cooper ME, Josefsson EC, Kile BT, Nagareddy PR, Murphy AJ. Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes. Arterioscler Thromb Vasc Biol 2021; 41:1167-1178. [PMID: 33441028 DOI: 10.1161/atvbaha.120.315369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-xL (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-xPlt20) or wild-type littermate controls into atherosclerotic-prone Ldlr+/- mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-xL function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-xPlt20 bone marrow transplanted Ldlr+/- mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-xL with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe-/- mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. CONCLUSIONS These studies suggest that selectively reducing circulating platelets, by targeting Bcl-xL to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.
Collapse
Affiliation(s)
- Man K S Lee
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Diabetes (M.K.S.L., N.M.J.H., O.D.C., M.E.C.), Monash University, Melbourne, Australia.,Department of Cardiometabolic Health (M.K.S.L., D.D., A.J.M.), University of Melbourne, Australia
| | - Michael J Kraakman
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.)
| | - Dragana Dragoljevic
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Cardiometabolic Health (M.K.S.L., D.D., A.J.M.), University of Melbourne, Australia
| | - Nordin M J Hanssen
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Diabetes (M.K.S.L., N.M.J.H., O.D.C., M.E.C.), Monash University, Melbourne, Australia.,Department of Internal Medicine, CARIM, School of Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands (N.M.J.H.).,Amsterdam Diabetes Centrum, Internal and vascular medicine, Amsterdam UMC, AMC, the Netherlands (N.M.J.H.)
| | - Michelle C Flynn
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Immunology (M.C.F., A.J.M.), Monash University, Melbourne, Australia
| | - Annas Al-Sharea
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.)
| | - Gopalkrishna Sreejit
- Division of Cardiac Surgery, Department of Surgery, Ohio State University, Columbus (G.S., P.R.N.)
| | - Camilla Bertuzzo-Veiga
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Physiology (C.B.-V., A.J.M.), University of Melbourne, Australia
| | - Olivia D Cooney
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Diabetes (M.K.S.L., N.M.J.H., O.D.C., M.E.C.), Monash University, Melbourne, Australia
| | - Fatima Baig
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.)
| | - Elizabeth Morriss
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.)
| | - Mark E Cooper
- Department of Diabetes (M.K.S.L., N.M.J.H., O.D.C., M.E.C.), Monash University, Melbourne, Australia
| | - Emma C Josefsson
- Department of Medical Biology (E.C.J.), University of Melbourne, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (E.C.J.)
| | - Benjamin T Kile
- Monash Biomedicine Discovery Institute (B.T.K.), Monash University, Melbourne, Australia.,Faculty of Health and Medical Sciences, University of Adelaide, Australia (B.T.K.)
| | - Prabhakara R Nagareddy
- Division of Cardiac Surgery, Department of Surgery, Ohio State University, Columbus (G.S., P.R.N.)
| | - Andrew J Murphy
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia (M.K.S.L., M.J.K., D.D., N.M.J.H., M.C.F., A.A.-S., C.B.-V., O.D.C., F.B., E.M., A.J.M.).,Department of Immunology (M.C.F., A.J.M.), Monash University, Melbourne, Australia.,Department of Cardiometabolic Health (M.K.S.L., D.D., A.J.M.), University of Melbourne, Australia.,Department of Physiology (C.B.-V., A.J.M.), University of Melbourne, Australia
| |
Collapse
|
|
20
|
Yao H, Sun Z, Zang G, Zhang L, Hou L, Shao C, Wang Z. Epidemiological Research Advances in Vascular Calcification in Diabetes. J Diabetes Res 2021; 2021:4461311. [PMID: 34631895 PMCID: PMC8500764 DOI: 10.1155/2021/4461311] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/27/2021] [Accepted: 09/11/2021] [Indexed: 12/29/2022] Open
Abstract
Vascular calcification is the transformation of arterial wall mesenchymal cells, particularly smooth muscle cells (SMCs), into osteoblast phenotypes by various pathological factors. Additionally, vascular transformation mediates the abnormal deposition of calcium salts in the vascular wall, such as intimal and media calcification. Various pathological types have been described, such as calcification and valve calcification. The incidence of vascular calcification in patients with diabetes is much higher than that in nondiabetic patients, representing a critical cause of cardiovascular events in patients with diabetes. Because basic research on the clinical transformation of vascular calcification has yet to be conducted, this study systematically expounds on the risk factors for vascular calcification, vascular bed differences, sex differences, ethnic differences, diagnosis, severity assessments, and treatments to facilitate the identification of a new entry point for basic research and subsequent clinical transformation regarding vascular calcification and corresponding clinical evaluation strategies.
Collapse
Affiliation(s)
- Haipeng Yao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guangyao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lina Hou
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
21
|
Konst RE, Guzik TJ, Kaski JC, Maas AHEM, Elias-Smale SE. The pathogenic role of coronary microvascular dysfunction in the setting of other cardiac or systemic conditions. Cardiovasc Res 2020; 116:817-828. [PMID: 31977015 PMCID: PMC7526753 DOI: 10.1093/cvr/cvaa009] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 12/09/2019] [Accepted: 01/21/2020] [Indexed: 12/13/2022] Open
Abstract
Coronary microvascular dysfunction (CMD) plays a pathogenic role in cardiac and systemic conditions other than microvascular angina. In this review, we provide an overview of the pathogenic role of CMD in the setting of diabetes mellitus, obesity, hypertensive pregnancy disorders, chronic inflammatory and autoimmune rheumatic disorders, chronic kidney disease, hypertrophic cardiomyopathy, and aortic valve stenosis. In these various conditions, CMD results from different structural, functional, and/or dynamic alterations in the coronary microcirculation associated with the primary disease process. CMD is often detectable very early in the course of the primary disease, before clinical symptoms or signs of myocardial ischaemia are present, and it portrays an increased risk for cardiovascular events.
Collapse
Affiliation(s)
- Regina E Konst
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Tomasz J Guzik
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, UK
| | - Juan-Carlos Kaski
- The Queen Elizabeth Hospital Discipline of Medicine, University of Adelaide, Central Adelaide Local Health Network, Coronary Vasomotion Disorders International Study Group (COVADIS), Adelaide, Australia.,Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK
| | - Angela H E M Maas
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Suzette E Elias-Smale
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| |
Collapse
|
|
22
|
Shin S, Claggett B, Pfeffer MA, Skali H, Liu J, Aguilar D, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Tardif J, Solomon SD. Hyperglycaemia, ejection fraction and the risk of heart failure or cardiovascular death in patients with type 2 diabetes and a recent acute coronary syndrome. Eur J Heart Fail 2020; 22:1133-1143. [DOI: 10.1002/ejhf.1790] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/25/2022] Open
Affiliation(s)
- Sung‐Hee Shin
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
- Inha University Incheon South Korea
| | - Brian Claggett
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | - Marc A. Pfeffer
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | | | - Jiankang Liu
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | - David Aguilar
- University of Texas Health Science Center Houston TX USA
| | - Rafael Diaz
- Estudios Clínicos Latinoamérica Rosario Argentina
| | - Kenneth Dickstein
- University of Bergen, Stavanger University Hospital Stavanger Norway
| | - Hertzel C. Gerstein
- Department of Medicine and Population Health Research Institute McMaster University and Hamilton Health Sciences Ontario Canada
| | - Lars V. Køber
- Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
| | | | - Eldrin F. Lewis
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | - Aldo P. Maggioni
- Research Center of the Italian Association of Hospital Cardiologists Florence Italy
| | - John J.V. McMurray
- British Heart Foundation Cardiovascular Research Centre University of Glasgow Glasgow UK
| | | | | | | | - Scott D. Solomon
- Cardiovascular Division Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | | |
Collapse
|
|
23
|
Yin Y, Chen F, Li J, Yang J, Li Q, Jin P. AURKA Enhances Autophagy of Adipose Derived Stem Cells to Promote Diabetic Wound Repair via Targeting FOXO3a. J Invest Dermatol 2020; 140:1639-1649.e4. [PMID: 32004564 DOI: 10.1016/j.jid.2019.12.032] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 12/09/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022]
Abstract
AURKA regulates apoptosis and autophagy in a diverse range of diseases and exhibits promising clinical efficacy; however, the role of AURKA in regulating adipose-derived stem cells (ADSCs) and repairing diabetic wound remains unclear. Here, we showed that ADSCs subjected to high glucose stress displayed an obvious induction of AURKA and FOXO3a, and a significant increase in autophagy and apoptosis. AURKA was confirmed to regulate autophagy through FOXO3a. AURKA-mediated autophagy inhibited high-glucose-induced apoptosis of ADSCs. Furthermore, co-immunoprecipitation and chromatin immunoprecipitation assays were employed to investigate the interaction of AURKA and FOXO3a. FOXO3a bound to its own promoter and transactivated its own expression. AURKA was found to interact with FOXO3a to regulate FOXO3a activity. In diabetic mice, ADSCs overexpressing AURKA led to a decrease of apoptosis of ADSCs and promoted wound healing in the skin. Taken together, our data suggest that transcriptional regulation of FOXO3a by high-glucose-mediated AURKA is necessary for ADSCs autophagy. Our data reveal a potential therapeutic strategy for targeting AURKA involved in high-glucose-induced anti-apoptotic autophagy in ADSCs.
Collapse
Affiliation(s)
- Yating Yin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Feifei Chen
- Jiangsu Center for the Collaboration and Innovation of Cancer, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Cancer Biotherapy Institute, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Jianhua Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jing Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Peisheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| |
Collapse
|
|
24
|
Li Y, Li Y, Yang T, Wang M. Dioscin attenuates oxLDL uptake and the inflammatory reaction of dendritic cells under high glucose conditions by blocking p38 MAPK. Mol Med Rep 2019; 21:304-310. [PMID: 31746382 PMCID: PMC6896274 DOI: 10.3892/mmr.2019.10806] [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: 04/08/2019] [Accepted: 10/15/2019] [Indexed: 12/26/2022] Open
Abstract
Dioscin has been shown to affect the regulation of metabolic diseases, including diabetes; however, the mechanism of action is still unclear. Under high glucose (HG) conditions, the expression of scavenger receptors and the uptake of oxidized low‑density lipoprotein (oxLDL) are upregulated in dendritic cells (DCs), which are critical steps in atherogenesis and inflammation. In this study, the focus was on the impact of dioscin on the function of DCs. Immature DCs were cultured with: 5.5 mM glucose medium (control group); 30 mM glucose medium (HG group); HG + 10 mM dioscin; HG + 20 mM dioscin; HG + 30 mM dioscin; and HG + 40 mM dioscin. For subsequent experiments, 30 mM dioscin was used as the experimental concentration. Dichlorodihydrofluorescein fluorescence was used to measure the intracellular production of reactive oxygen species (ROS) in DCs. The expression levels of the scavenger receptors, including class A scavenger receptors (SR‑A), CD36 and lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1) were determined via quantitative PCR. The protein expression of p38 mitogen‑activated protein kinase (MAPK) was determined by western blotting. Furthermore, ELISA was used to detect the levels of interleukin (IL)‑6, IL‑10 and IL‑12. Finally, DCs were incubated with diOlistic (Dil)‑labeled oxLDL, and flow cytometry analysis was used to investigate the Dil‑oxLDL‑incorporated fraction. The incubation of DCs with dioscin inhibited the induction of ROS production, in a dose‑dependent manner, under HG conditions. The upregulation of SR‑A, CD36 and LOX‑1 genes was partially abolished by dioscin, which also partially reversed p38 MAPK protein upregulation. Furthermore, increased secretion of IL‑6 and IL‑12, and decreased secretion of IL‑10 in DCs, induced by HG, was also reversed by dioscin. To conclude, dioscin could attenuate the production of ROS, inflammatory cytokine secretion and oxLDL uptake by DCs in HG conditions by preventing the expression of scavenger receptors and p38 MAPK, thus playing a positive role in preventing atherogenesis.
Collapse
Affiliation(s)
- Ying Li
- Cardiovascular Department, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, P.R. China
| | - Yong Li
- Cardiovascular Department, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, P.R. China
| | - Te Yang
- Cardiovascular Department, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, P.R. China
| | - Ming Wang
- Cardiovascular Department, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, P.R. China
| |
Collapse
|
|
25
|
Andreeva–Gateva PA, Mihaleva ID, Dimova II. Type 2 diabetes mellitus and cardiovascular risk; what the pharmacotherapy can change through the epigenetics. Postgrad Med 2019; 132:109-125. [DOI: 10.1080/00325481.2019.1681215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Pavlina A. Andreeva–Gateva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
- Department of Pharmacology, Medical Faculty, Sofia University “St Kliment Ohridski”, Sofia, Bulgaria
| | - Ivelina D. Mihaleva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Ivanka I. Dimova
- Department of Medical Genetics, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
| |
Collapse
|
|
26
|
Lee CH, Hsieh MJ, Chang SH, Hung KC, Wang CJ, Hsu MY, Juang JH, Hsieh IC, Wen MS, Liu SJ. Nanofibrous vildagliptin-eluting stents enhance re-endothelialization and reduce neointimal formation in diabetes: in vitro and in vivo. Int J Nanomedicine 2019; 14:7503-7513. [PMID: 31686818 PMCID: PMC6751553 DOI: 10.2147/ijn.s211898] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 07/16/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The high lifetime risk of vascular disease is one of the important issues that plague patients with diabetes mellitus. Systemic oral vildagliptin administration favors endothelial recovery and inhibits smooth muscle cell (SMC) proliferation. However, the localized release of vildagliptin in the diabetic vessel damage has seldom been investigated. RESEARCH DESIGN AND METHODS In this work, nanofiber-eluting stents that loaded with vildagliptin, a dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor, was fabricated to treat diabetic vascular disease. To prepare nanofibers, the poly (D,L)-lactide-co-glycolide (PLGA) and vildagliptin were mixed using hexafluoroisopropanol and electrospinning process. In vitro and in vivo release rates of the vildagliptin were characterized using high-performance liquid chromatography. RESULTS Effective vildagliptin concentrations were delivered for more than 28 days from the nanofibrous membranes coating on the surface of the stents in vitro and in vivo. The vildagliptin-eluting PLGA membranes greatly accelerated the recovery of diabetic endothelia and reduced SMC hyperplasia. The type I collagen content of the diabetic vascular intimal area that was treated by vildagliptin-eluting stents was lower than that of the non-vildagliptin-eluting group. CONCLUSION The experimental results revealed that stenting with vildagliptin-eluting PLGA membranes could potentially promote healing for diabetic arterial diseases.
Collapse
Affiliation(s)
- Chen-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Ming-Jer Hsieh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Shang-Hung Chang
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Kuo-Chun Hung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Chao-Jan Wang
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan
| | - Ming-Yi Hsu
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan
| | - Jyuhn-Huarng Juang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - I-Chang Hsieh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Ming-Shien Wen
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan
| | - Shih-Jung Liu
- Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan33305, Taiwan
| |
Collapse
|
|
27
|
Shalash MAM, Rohoma KH, Kandil NS, Abdel Mohsen MA, Taha AAF. Serum sclerostin level and its relation to subclinical atherosclerosis in subjects with type 2 diabetes. J Diabetes Complications 2019; 33:592-597. [PMID: 31129005 DOI: 10.1016/j.jdiacomp.2019.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/18/2019] [Accepted: 04/21/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND Sclerostin, a Wnt-signalling inhibitor, is an established negative regulator of bone formation. However, data regarding its potential importance in vascular disease are less clear. Common carotid artery media thickness (CIMT) assessment and plaque identification using ultrasound imaging are well-recognized tools for identifying and monitoring atherosclerosis. The aim of the present study is to examine the relationship between serum sclerostin and subclinical atherosclerosis (as evidenced by CIMT). METHODS This cross-sectional study included 50 subjects with T2DM and 20 subjects as a control group. Multivariable linear regression models were used to assess the association of sclerostin with subclinical atherosclerosis. RESULTS Serum sclerostin levels in T2DM patients were significantly higher compared to the control group (167.16 ± 63.60 versus 85.98 ± 23.74 pg/ml, P < 0.0001). A concentration of ≥162.5 pg/ml showed a sensitivity of 90% and a specificity of 86.67% to detect an increased risk of subclinical atherosclerosis. Univariate analysis revealed a significant positive correlation between serum sclerostin and CIMT (r = 0.635, P < 0.001). Sclerostin concentrations remained independently associated with CIMT (β = 63.188 [6.919-119.456], P = 0.017) after adjusting for age and gender. CONCLUSION Our data suggest a positive correlation between serum sclerostin level and subclinical atherosclerosis in subjects with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Magui Abdel Moneim Shalash
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Kamel Hemida Rohoma
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Noha Said Kandil
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | | | - Aya Abdul Fattah Taha
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
28
|
Seleem M, Shabayek M, Ewida HA. MicroRNAs 342 and 450 together with NOX-4 activity and their association with coronary artery disease in diabetes. Diabetes Metab Res Rev 2019; 35:e3130. [PMID: 30681251 DOI: 10.1002/dmrr.3130] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 01/15/2019] [Accepted: 01/17/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Dysregulation of miRNAs has been associated with many clinical conditions, including coronary artery disease (CAD). MiRNAs roles in patients with type 2 diabetes mellitus (T2D) with or without CAD, however, have not been clearly understood. Therefore we studied the expression of miRNAs 342 and 450 and the activity of the NADPH oxidase 4 (NOX-4), and their association with anthropometric and biochemical parameters of hyperglycaemia and dyslipidaemia. SUBJECTS AND METHODS Blood was collected from 200 outpatient subjects, divided into four groups of 50 individuals including control, T2D, CAD, and T2D with CAD. CAD was further divided based on CAD with angina, CAD clots, and CAD ischaemia to differentiate the primary cause of CAD. We measured the miRNAs 342 and 450 expression and NOX-4 activity, in addition to routine parameters. RESULTS The expression of miRNAs 342 and 450 and NOX-4 activity was significantly different between groups. Furthermore, they presented significant correlations with routine parameters, providing evidence of a potentially beneficial role in stratifying the risk for CAD in patients with T2D. CONCLUSION The results of this study suggest that the expression of miRNAs 342 and 450 and NOX-4 activity may help identify those individuals with T2D at high risk for developing CAD as well as the prognosis in those with established CAD.
Collapse
Affiliation(s)
- Mae Seleem
- Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Marwa Shabayek
- Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Heba A Ewida
- Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| |
Collapse
|
|
29
|
Affiliation(s)
- Karin E Bornfeldt
- From the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition and Department of Pathology, UW Diabetes Institute, University of Washington School of Medicine, Seattle.
| |
Collapse
|
|
30
|
Recovery of Cardiac Remodeling and Dysmetabolism by Pancreatic Islet Injury Improvement in Diabetic Rats after Yacon Leaf Extract Treatment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1821359. [PMID: 30057670 PMCID: PMC6051012 DOI: 10.1155/2018/1821359] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/12/2018] [Indexed: 02/06/2023]
Abstract
Yacon (Smallanthus sonchifolius) is a native Andean plant rich in phenolic compounds, and its effects on dysmetabolism and cardiomyopathy in diabetic rats was evaluated. The rats (10/group) were allocated as follows: C, controls; C + Y, controls treated with Yacon leaf extract (YLE); DM, diabetic controls; and DM + Y, diabetic rats treated with YLE. Type 1 diabetes (T1DM) was induced by the administration of streptozotocin (STZ; 40 mg−1/kg body weight, single dose, i.p.), and treated groups received 100 mg/kg body weight YLE daily via gavage for 30 d. The YLE group shows an improvement in dysmetabolism and cardiomyopathy in the diabetic condition (DM versus DM + Y) promoting a significant reduction of glycemia by 63.39%, an increase in insulin concentration by 49.30%, and a decrease in serum triacylglycerol and fatty acid contents by 0.39- and 0.43-fold, respectively, by ameliorating the pancreatic islet injury, as well as increasing the activity of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and decreasing the fibrosis and cellular disorganization in cardiac tissue. The apparent benefits of YLE seem to be mediated by ameliorating dysmetabolism and oxidative stress in pancreatic and cardiac tissues.
Collapse
|
|
31
|
Hien TT, Garcia‐Vaz E, Stenkula KG, Sjögren J, Nilsson J, Gomez MF, Albinsson S. MicroRNA‐dependent regulation of KLF4 by glucose in vascular smooth muscle. J Cell Physiol 2018; 233:7195-7205. [DOI: 10.1002/jcp.26549] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 02/12/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Tran T. Hien
- Department of Experimental Medical ScienceLund UniversityLundSweden
| | - Eliana Garcia‐Vaz
- Department of Clinical Sciences in Malmö, Lund University Diabetes CentreLund UniversitySweden
| | | | - Johan Sjögren
- Department of Cardiothoracic SurgerySkåne University Hospital and Lund UniversityLundSweden
| | - Johan Nilsson
- Department of Cardiothoracic SurgerySkåne University Hospital and Lund UniversityLundSweden
| | - Maria F. Gomez
- Department of Clinical Sciences in Malmö, Lund University Diabetes CentreLund UniversitySweden
| | | |
Collapse
|
|
32
|
Hsiu H, Hu HF, Tsai HC. Differences in laser-Doppler indices between skin-surface measurement sites in subjects with diabetes. Microvasc Res 2018; 115:1-7. [DOI: 10.1016/j.mvr.2017.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/23/2017] [Accepted: 07/24/2017] [Indexed: 12/17/2022]
|
|
33
|
Constitutive modeling of human femoropopliteal artery biaxial stiffening due to aging and diabetes. Acta Biomater 2017; 64:50-58. [PMID: 28974476 DOI: 10.1016/j.actbio.2017.09.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 09/21/2017] [Accepted: 09/29/2017] [Indexed: 12/17/2022]
Abstract
Atherosclerotic obstructive disease of the femoropopliteal artery (Peripheral Arterial Disease, PAD) is notorious for high treatment failure rates. Older age and diabetes mellitus (DM) are among the major risk factors for PAD, and both are associated with increased arterial stiffness. Our goal was to develop a constitutive model describing multiaxial arterial stiffening, and use it to portray aging of normal and diabetic human femoropopliteal arteries (FPA). Fresh human FPAs (n=744) were obtained from 13-82-year-old donors. Arteries were tested using planar biaxial extension, and their behavior was modeled with a constitutive relation that included stiffening functions of age. FPA diameter, wall thickness, circumferential, and longitudinal opening angles increased with age, while longitudinal pre-stretch decreased. Diameter and circumferential opening angle did not change with age in subjects with DM. Younger FPAs were more compliant longitudinally but became more isotropic with age. Arteries with DM stiffened significantly faster in the circumferential direction than arteries without DM. Constitutive model accurately portrayed orthotropic stiffening with age of both normal and diabetic arteries. Constitutive description of FPA aging contributes to understanding of arterial pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in PAD repair by providing more personalized arterial properties. STATEMENT OF SIGNIFICANCE We have analyzed n=744 human femoropopliteal artery (FPA) specimens using biaxial tensile testing to derive constitutive description of FPA aging in diabetic and non-diabetic subjects. The proposed model allows determination of FPA mechanical properties for subjects of any given age in the range of 13-82years. These results contribute to understanding of FPA pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in peripheral arterial disease repair by providing more personalized arterial properties. In addition, they can guide the development of new materials tunable to diabetic and non-diabetic arteries.
Collapse
|
|
34
|
Thrombogenicity and central pulse pressure to enhance prediction of ischemic event occurrence in patients with established coronary artery disease: The MAGMA-ischemia score. Atherosclerosis 2017; 268:55-62. [PMID: 29175655 DOI: 10.1016/j.atherosclerosis.2017.11.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 10/20/2017] [Accepted: 11/16/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Conventional cardiovascular risk estimators based on clinical demographics have limited prediction of coronary events. Markers for thrombogenicity and vascular function have not been explored in risk estimation of high-risk patients with coronary artery disease. We aimed to develop a clinical and biomarker score to predict 3-year adverse cardiovascular events. METHODS Four hundred eleven patients, with ejection fraction ≥40% undergoing coronary angiography, and found to have a luminal diameter stenosis ≥50%, were included in the analysis. Thrombelastography indices and central pulse pressure (CPP) were determined at the time of catheterization. RESULTS We identified predictors of death, myocardial infarction (MI) or stroke and developed a numerical ischemia risk score. The primary endpoint of cardiovascular death, MI or stroke occurred in 22 patients (5.4%). The factors associated with events were age, prior PCI or CABG, diabetes, CPP, and thrombin-induced platelet-fibrin clot strength, and were included in the MAGMA-ischemia score. The MAGMA-ischemia score showed a c-statistic of 0.85 (95% Confidence Interval [CI] 0.80-0.87; p<0.001) for the primary endpoint. In the subset of patients who underwent revascularization, the c-statistic was 0.90 (p<0.001). Patients with MAGMA-ischemia score greater than 5 had highest risk to develop clinical events, hazard ratio for the primary endpoint: 13.9 (95% CI 5.8-33.1, p<0.001) and for the secondary endpoint: 4.8 (95% CI 2.3-9.6, p<0.001). When compared to previous models, the MAGMA-ischemia score yielded a higher discrimination. CONCLUSIONS Inclusion of CPP and assessment of thrombogenicity in a novel score for patients with documented CAD enhanced the prediction of events.
Collapse
|
|
35
|
Yang L, Gao L, Nickel T, Yang J, Zhou J, Gilbertsen A, Geng Z, Johnson C, Young B, Henke C, Gourley GR, Zhang J. Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells. Circ Res 2017; 121:1251-1262. [PMID: 29021296 DOI: 10.1161/circresaha.117.311819] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/05/2017] [Accepted: 10/10/2017] [Indexed: 01/04/2023]
Abstract
RATIONALE The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. OBJECTIVE To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. METHODS AND RESULTS Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L-) medium. Compared with the L- medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues. CONCLUSIONS These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.
Collapse
Affiliation(s)
- Libang Yang
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Ling Gao
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Thomas Nickel
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Jing Yang
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Jingyi Zhou
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Adam Gilbertsen
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Zhaohui Geng
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Caitlin Johnson
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Bernice Young
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Craig Henke
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Glenn R Gourley
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China
| | - Jianyi Zhang
- From the Division of Cardiology, Department of Medicine (L.Y., T.N., C.J., B.Y.), Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (A.G., C.H., Z.G.) and Department of Paediatrics (G.R.G.), University of Minnesota Medical School, Minneapolis; Department of Biomedical Engineering, University of Alabama at Birmingham (L.G., J.Z.); and Department of Infectious Disease, Renmin Hospital (J.Y.) and Department of Microbiology, School of Basic Medical Science (J.Y., J.Z.), Hubei University of Medicine, Shiyan, China.
| |
Collapse
|
|
36
|
Brennan E, Wang B, McClelland A, Mohan M, Marai M, Beuscart O, Derouiche S, Gray S, Pickering R, Tikellis C, de Gaetano M, Barry M, Belton O, Ali-Shah ST, Guiry P, Jandeleit-Dahm KAM, Cooper ME, Godson C, Kantharidis P. Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis. Diabetes 2017; 66:2266-2277. [PMID: 28487436 DOI: 10.2337/db16-1405] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/30/2017] [Indexed: 12/15/2022]
Abstract
The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE-/- mouse. In vitro platelet-derived growth factor (PDGF)- and tumor necrosis factor-α (TNF-α)-induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A4), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.
Collapse
Affiliation(s)
- Eoin Brennan
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Diabetes Complications Research Centre, Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
| | - Bo Wang
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Anatomy and Developmental Biology, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Aaron McClelland
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Muthukumar Mohan
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Mariam Marai
- Diabetes Complications Research Centre, Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
| | - Ophelie Beuscart
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Sinda Derouiche
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Stephen Gray
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Raelene Pickering
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Chris Tikellis
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Monica de Gaetano
- Diabetes Complications Research Centre, Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
| | - Mary Barry
- St. Vincent's University Hospital, Dublin, Ireland
| | - Orina Belton
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Syed Tasadaque Ali-Shah
- Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin, Ireland
| | - Patrick Guiry
- Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin, Ireland
| | - Karin A M Jandeleit-Dahm
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Mark E Cooper
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Catherine Godson
- Diabetes Complications Research Centre, Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
| | - Phillip Kantharidis
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
| |
Collapse
|
|
37
|
Keating ST, Plutzky J, El-Osta A. Epigenetic Changes in Diabetes and Cardiovascular Risk. Circ Res 2017; 118:1706-22. [PMID: 27230637 DOI: 10.1161/circresaha.116.306819] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 04/30/2016] [Indexed: 01/03/2023]
Abstract
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.
Collapse
Affiliation(s)
- Samuel T Keating
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.)
| | - Jorge Plutzky
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.)
| | - Assam El-Osta
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.).
| |
Collapse
|
|
38
|
Dubský M, Jirkovská A, Bem R, Nemcová A, Fejfarová V, Jude EB. Cell therapy of critical limb ischemia in diabetic patients - State of art. Diabetes Res Clin Pract 2017; 126:263-271. [PMID: 28288436 DOI: 10.1016/j.diabres.2017.02.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/19/2016] [Accepted: 02/22/2017] [Indexed: 01/15/2023]
Abstract
In this review we report on the state of cell therapy of critical limb ischemia (CLI) with respect to differences between diabetic and non-diabetic patients mainly from the clinical point of view. CLI is the most severe form of peripheral arterial disease and its diagnosis and treatment in diabetic patients is very difficult. The therapeutic effect of standard methods of CLI treatment is only partial - more than one third of diabetic patients are not eligible for standard revascularization; therefore, new therapeutic techniques such as cell therapy have been studied in clinical trials. Presence of CLI in patients with diabetic foot disease is associated with worse clinical outcomes such as lack of healing of foot ulcers, major amputations and premature mortality. A revascularization procedure cannot be successful as the only method in contrast to patients without diabetes, but it must always be part of a complex therapy focused not only on ischemia, but also on treatment of infection, off-loading, metabolic control of diabetes and nutrition, local therapy, etc. Therefore, the main criteria for cell therapy may vary in diabetic patients and non-diabetic persons and results of this treatment method should always be assessed in the context of ensuring comprehensive therapy. This review carries out an analysis of the source of precursor cells, route of administration and brings a brief report of published data with respect to diabetic and non-diabetic patients and our experience with autologous cell therapy of diabetic patients with CLI. Analysis of the studies in terms of diabetes is difficult, because in most of them sub-analysis for diabetic patients is not performed separately. The other problem is that it is not clear if diabetic patients received adequate complex treatment for their foot ulcers which can strongly affect the rate of major amputation as an outcome of CLI treatment.
Collapse
Affiliation(s)
- Michal Dubský
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
| | | | - Robert Bem
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Andrea Nemcová
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | | | - Edward B Jude
- Diabetes Centre, Tameside Hospital NHS Foundation Trust and University of Manchester, Lancashire, UK
| |
Collapse
|
|
39
|
|
|
40
|
Harith HH, Di Bartolo BA, Cartland SP, Genner S, Kavurma MM. Insulin promotes vascular smooth muscle cell proliferation and apoptosis via differential regulation of tumor necrosis factor-related apoptosis-inducing ligand. J Diabetes 2016; 8:568-78. [PMID: 26333348 DOI: 10.1111/1753-0407.12339] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 08/12/2015] [Accepted: 08/29/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Insulin regulates glucose homeostasis but can also promote vascular smooth muscle (VSMC) proliferation, important in atherogenesis. Recently, we showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stimulates intimal thickening via accelerated growth of VSMCs. The aim of the present study was to determine whether insulin-induced effects on VSMCs occur via TRAIL. METHODS Expression of TRAIL and TRAIL receptor in response to insulin and glucose was determined by polymerase chain reaction. Transcriptional activity was assessed using wild-type and site-specific mutations of the TRAIL promoter. Chromatin immunoprecipitation studies were performed. VSMC proliferation and apoptosis was measured. RESULTS Insulin and glucose exposure to VSMC for 24 h stimulated TRAIL mRNA expression. This was also evident at the transcriptional level. Both insulin- and glucose-inducible TRAIL transcriptional activity was blocked by dominant-negative specificity protein-1 (Sp1) overexpression. There are five functional Sp1-binding elements (Sp1-1, Sp1-2, Sp-5/6 and Sp1-7) on the TRAIL promoter. Insulin required the Sp1-1 and Sp1-2 sites, but glucose needed all Sp1-binding sites to induce transcription. Furthermore, insulin (but not glucose) was able to promote VSMC proliferation over time, associated with increased decoy receptor-2 (DcR2) expression. In contrast, chronic 5-day exposure of VSMC to 1 µg/mL insulin repressed TRAIL and DcR2 expression, and reduced Sp1 enrichment on the TRAIL promoter. This was associated with increased cell death. CONCLUSIONS The findings of the present study provide a new mechanistic insight into how TRAIL is regulated by insulin. This may have significant implications at different stages of diabetes-associated cardiovascular disease. Thus, TRAIL may offer a novel therapeutic solution to combat insulin-induced vascular pathologies.
Collapse
MESH Headings
- Animals
- Apoptosis/drug effects
- Blotting, Western
- Cell Proliferation/drug effects
- Cells, Cultured
- Dose-Response Relationship, Drug
- Gene Expression Regulation/drug effects
- Glucose/pharmacology
- Humans
- Hypoglycemic Agents/pharmacology
- Insulin/pharmacology
- Mice, Knockout
- Muscle, Smooth, Vascular/cytology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Rats, Inbred WKY
- Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics
- Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- TNF-Related Apoptosis-Inducing Ligand/genetics
- TNF-Related Apoptosis-Inducing Ligand/metabolism
Collapse
Affiliation(s)
- Hanis H Harith
- Centre for Vascular Research
- School of Medical Sciences UNSW, Australia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Belinda A Di Bartolo
- The Heart Research Institute
- The University of Sydney, Sydney, New South Wales, Australia
| | - Siân P Cartland
- The Heart Research Institute
- The University of Sydney, Sydney, New South Wales, Australia
| | | | - Mary M Kavurma
- The Heart Research Institute
- The University of Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
|
41
|
Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations. Circulation 2016; 133:2459-502. [PMID: 27297342 PMCID: PMC4910510 DOI: 10.1161/circulationaha.116.022194] [Citation(s) in RCA: 713] [Impact Index Per Article: 79.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.
Collapse
Affiliation(s)
- Cecilia C Low Wang
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - Connie N Hess
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - William R Hiatt
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - Allison B Goldfine
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.).
| |
Collapse
|
|
42
|
Peiró C, Romacho T, Azcutia V, Villalobos L, Fernández E, Bolaños JP, Moncada S, Sánchez-Ferrer CF. Inflammation, glucose, and vascular cell damage: the role of the pentose phosphate pathway. Cardiovasc Diabetol 2016; 15:82. [PMID: 27245224 PMCID: PMC4888494 DOI: 10.1186/s12933-016-0397-2] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/12/2016] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Hyperglycemia is acknowledged as a pro-inflammatory condition and a major cause of vascular damage. Nevertheless, we have previously described that high glucose only promotes inflammation in human vascular cells previously primed with pro-inflammatory stimuli, such as the cytokine interleukin (IL)1β. Here, we aimed to identify the cellular mechanisms by which high glucose exacerbates the vascular inflammation induced by IL1β. METHODS Cultured human aortic smooth muscle cells (HASMC) and isolated rat mesenteric microvessels were treated with IL1β in medium containing 5.5-22 mmol/L glucose. Glucose uptake and consumption, lactate production, GLUT1 levels, NADPH oxidase activity and inflammatory signalling (nuclear factor-κB activation and inducible nitric oxide synthase expression) were measured in HASMC, while endothelium-dependent relaxations to acetylcholine were determined in rat microvessels. Pharmacological inhibition of IL1 receptors, NADPH oxidase and glucose-6-phosphate dehydrogenase (G6PD), as well as silencing of G6PD, were also performed. Moreover, the pentose phosphate pathway (PPP) activity and the levels of reduced glutathione were determined. RESULTS We found that excess glucose uptake in HASMC cultured in 22 mM glucose only occurred following activation with IL1β. However, the simple entry of glucose was not enough to be deleterious since over-expression of the glucose transporter GLUT1 or increased glucose uptake following inhibition of mitochondrial respiration by sodium azide was not sufficient to trigger inflammatory mechanisms. In fact, besides allowing glucose entry, IL1β activated the PPP, thus permitting some of the excess glucose to be metabolized via this route. This in turn led to an over-activation NADPH oxidase, resulting in increased generation of free radicals and the subsequent downstream pro-inflammatory signalling. Moreover, in rat mesenteric microvessels high glucose incubation enhanced the endothelial dysfunction induced by IL1β by a mechanism which was abrogated by the inhibition of the PPP. CONCLUSIONS A pro-inflammatory stimulus like IL1β transforms excess glucose into a vascular deleterious agent by causing an increase in glucose uptake and its subsequent diversion into the PPP, promoting the pro-oxidant conditions required for the exacerbation of pro-oxidant and pro-inflammatory pathways. We propose that over-activation of the PPP is a crucial mechanism for the vascular damage associated to hyperglycemia.
Collapse
Affiliation(s)
- Concepción Peiró
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 29029, Madrid, Spain
| | - Tania Romacho
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 29029, Madrid, Spain.,Paul Langerhans-Group, Integrative Physiology, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany
| | - Verónica Azcutia
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 29029, Madrid, Spain.,Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Laura Villalobos
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 29029, Madrid, Spain
| | - Emilio Fernández
- Instituto de Biología Funcional y Genómica, Universidad de Salamanca-CSIC, 37007, Salamanca, Spain
| | - Juan P Bolaños
- Instituto de Biología Funcional y Genómica, Universidad de Salamanca-CSIC, 37007, Salamanca, Spain
| | - Salvador Moncada
- Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, UK. .,Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, UK.
| | - Carlos F Sánchez-Ferrer
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 29029, Madrid, Spain.
| |
Collapse
|
|
43
|
Sun A, Wang Y, Liu J, Yu X, Sun Y, Yang F, Dong S, Wu J, Zhao Y, Xu C, Lu F, Zhang W. Exogenous H2S modulates mitochondrial fusion-fission to inhibit vascular smooth muscle cell proliferation in a hyperglycemic state. Cell Biosci 2016; 6:36. [PMID: 27252826 PMCID: PMC4888644 DOI: 10.1186/s13578-016-0102-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 05/09/2016] [Indexed: 11/24/2022] Open
Abstract
Aim Vascular smooth muscle cell (VSMC) proliferation in response to hyperglycemia is an important process in the development of arterial vessel hyperplasia. The shape change of mitochondria is dynamic and closely related to fission and fusion. Hydrogen sulfide (H2S) was confirmed to have anti-oxidative, anti-inflammatory and anti-proliferative effects. However, little it is known about its effects on mitochondrial morphology induced by hyperglycemia. The aim of the study is to demonstrate that H2S inhibits VSMC proliferation through regulating mitochondrial fission. Methods and results We observe lower H2S levels as well as higher proliferative protein expression levels for proliferative cell nuclear antigen (PCNA) and cyclin D1 and higher mitochondrial fusion–fission protein expression levels for dynamin-related protein 1 (Drp 1) in human kidney arteries and in db/db mouse aorta. Exogenous H2S (100 μM NaHS) inhibits vascular smooth muscle cells of human pulmonary aorta(HPASMC) proliferation and migration in response to high glucose using the BrdU and scratch wound repair assays, decreases proliferative protein (PCNA and cyclin D1) expression, and reduces ROS production in the cytoplasm and mitochondria. When HPASMCs proliferate with a high glucose treatment, the mitochondria become small spheres with a short rod-shaped structure, whereas NaHS, a mitochondrial division inhibitor and siDrp prevent VSMC proliferation and maintain mitochondria as stationary and randomly dispersed with fixed structures. Conclusion Exogenous H2S aids in inhibiting mitochondrial fragmentation and affects proliferation in db/db mice and HPASMCs by decreasing Drp 1 expression. Electronic supplementary material The online version of this article (doi:10.1186/s13578-016-0102-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Aili Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Yan Wang
- Department of Urologic Surgery, First Clinical Medical School of Harbin Medical University, Harbin, 150001 China
| | - Jiaqi Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Xiangjing Yu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Yu Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Fan Yang
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Shiyun Dong
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Jichao Wu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Yajun Zhao
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Changqing Xu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Fanghao Lu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| | - Weihua Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, 150086 China
| |
Collapse
|
|
44
|
Kayama Y, Raaz U, Jagger A, Adam M, Schellinger IN, Sakamoto M, Suzuki H, Toyama K, Spin JM, Tsao PS. Diabetic Cardiovascular Disease Induced by Oxidative Stress. Int J Mol Sci 2015; 16:25234-63. [PMID: 26512646 PMCID: PMC4632800 DOI: 10.3390/ijms161025234] [Citation(s) in RCA: 276] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 09/30/2015] [Accepted: 09/30/2015] [Indexed: 01/10/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.
Collapse
Affiliation(s)
- Yosuke Kayama
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Uwe Raaz
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Ann Jagger
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Matti Adam
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Isabel N Schellinger
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Masaya Sakamoto
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minatoku, Tokyo 105-0003, Japan.
| | - Hirofumi Suzuki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minatoku, Tokyo 105-0003, Japan.
| | - Kensuke Toyama
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Joshua M Spin
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Philip S Tsao
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| |
Collapse
|
|
45
|
Molecular Pathways Regulating Macrovascular Pathology and Vascular Smooth Muscle Cells Phenotype in Type 2 Diabetes. Int J Mol Sci 2015; 16:24353-68. [PMID: 26473856 PMCID: PMC4632754 DOI: 10.3390/ijms161024353] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/21/2015] [Accepted: 10/08/2015] [Indexed: 12/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a disease reaching a pandemic proportion in developed countries and a major risk factor for almost all cardiovascular diseases and their adverse clinical manifestations. T2DM leads to several macrovascular and microvascular alterations that influence the progression of cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are fundamental players in macrovascular alterations of T2DM patients. VSMCs display phenotypic and functional alterations that reflect an altered intracellular biomolecular scenario of great vessels of T2DM patients. Hyperglycemia itself and through intraparietal accumulation of advanced glycation-end products (AGEs) activate different pathways, in particular nuclear factor-κB and MAPKs, while insulin and insulin growth-factor receptors (IGFR) are implicated in the activation of Akt and extracellular-signal-regulated kinases (ERK) 1/2. Nuclear factor-κB is also responsible of increased susceptibility of VSMCs to pro-apoptotic stimuli. Down-regulation of insulin growth-factor 1 receptors (IGFR-1R) activity in diabetic vessels also influences negatively miR-133a levels, so increasing apoptotic susceptibility of VSMCs. Alterations of those bimolecular pathways and related genes associate to the prevalence of a synthetic phenotype of VSMCs induces extracellular matrix alterations of great vessels. A better knowledge of those biomolecular pathways and related genes in VSMCs will help to understand the mechanisms leading to macrovascular alterations in T2DM patients and to suggest new targeted therapies.
Collapse
|
|
46
|
Thiruvoipati T, Kielhorn CE, Armstrong EJ. Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes. World J Diabetes 2015; 6:961-969. [PMID: 26185603 PMCID: PMC4499529 DOI: 10.4239/wjd.v6.i7.961] [Citation(s) in RCA: 237] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/20/2014] [Accepted: 04/02/2015] [Indexed: 02/05/2023] Open
Abstract
Peripheral artery disease (PAD) is the atherosclerosis of lower extremity arteries and is also associated with atherothrombosis of other vascular beds, including the cardiovascular and cerebrovascular systems. The presence of diabetes mellitus greatly increases the risk of PAD, as well as accelerates its course, making these patients more susceptible to ischemic events and impaired functional status compared to patients without diabetes. To minimize these cardiovascular risks it is critical to understand the pathophysiology of atherosclerosis in diabetic patients. This, in turn, can offer insights into the therapeutic avenues available for these patients. This article provides an overview of the epidemiology of PAD in diabetic patients, followed by an analysis of the mechanisms by which altered metabolism in diabetes promotes atherosclerosis and plaque instability. Outcomes of PAD in diabetic patients are also discussed, with a focus on diabetic ulcers and critical limb ischemia.
Collapse
|
|
47
|
Nichols TC, Merricks EP, Bellinger DA, Raymer RA, Yu J, Lam D, Koch GG, Busby WH, Clemmons DR. Oxidized LDL and Fructosamine Associated with Severity of Coronary Artery Atherosclerosis in Insulin Resistant Pigs Fed a High Fat/High NaCl Diet. PLoS One 2015; 10:e0132302. [PMID: 26147990 PMCID: PMC4492503 DOI: 10.1371/journal.pone.0132302] [Citation(s) in RCA: 8] [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: 01/14/2015] [Accepted: 06/11/2015] [Indexed: 12/22/2022] Open
Abstract
Background Insulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown. Research Objective To determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet. Key Methods The primary endpoint was severity of coronary atherosclerosis in adult pigs (Sus scrofa, n = 37) fed a high fat diet that also contained high NaCl (56% above recommended levels) for 1 year. Principal Findings Twenty pigs developed severe and diffuse distal coronary artery atherosclerosis (i.e., severe = intimal area as a percent medial area > 200% in at least 2 coronary artery cross sections and diffuse distal = intimal area as a percent medial area ≥ 150% over 3 sections separated by 2 cm in the distal half of the coronary artery). The other 17 pigs had substantially less coronary artery atherosclerosis. All 37 pigs had blood pressure in a range that would be considered hypertensive in humans and developed elevations in total and LDL and HDL cholesterol, weight gain, increased backfat, and increased insulin resistance (Bergman Si) without overt diabetes. Insulin resistance was not associated with atherosclerosis severity. Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis. Most importantly, the 20 high fat/high NaCl diet -fed pigs with severe and diffuse distal coronary artery atherosclerosis had substantially greater increases (p< 0.05) in oxidized LDL (oxLDL) and fructosamine consistent with increased protein glycation. Conclusion In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.
Collapse
Affiliation(s)
- Timothy C. Nichols
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
| | - Elizabeth P. Merricks
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Dwight A. Bellinger
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Robin A. Raymer
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Jing Yu
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Diana Lam
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Gary G. Koch
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Walker H. Busby
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - David R. Clemmons
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| |
Collapse
|
|
48
|
Abstract
Despite the wealth of pre-clinical support for a role for reactive oxygen and nitrogen species (ROS/RNS) in the aetiology of diabetic complications, enthusiasm for antioxidant therapeutic approaches has been dampened by less favourable outcomes in large clinical trials. This has necessitated a re-evaluation of pre-clinical evidence and a more rational approach to antioxidant therapy. The present review considers current evidence, from both pre-clinical and clinical studies, to address the benefits of antioxidant therapy. The main focus of the present review is on the effects of direct targeting of ROS-producing enzymes, the bolstering of antioxidant defences and mechanisms to improve nitric oxide availability. Current evidence suggests that a more nuanced approach to antioxidant therapy is more likely to yield positive reductions in end-organ injury, with considerations required for the types of ROS/RNS involved, the timing and dosage of antioxidant therapy, and the selective targeting of cell populations. This is likely to influence future strategies to lessen the burden of diabetic complications such as diabetes-associated atherosclerosis, diabetic nephropathy and diabetic retinopathy.
Collapse
|
|
49
|
Yongming P, Zhaowei C, Yichao M, Keyan Z, Liang C, Fangming C, Xiaoping X, Quanxin M, Minli C. Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet. Cardiovasc Diabetol 2015; 14:6. [PMID: 25592139 PMCID: PMC4300051 DOI: 10.1186/s12933-014-0165-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 12/27/2014] [Indexed: 11/10/2022] Open
Abstract
Background A long-term high-fat/cholesterol (HFC) diet leads to insulin resistance (IR), which is associated with inflammation, atherosclerosis (AS), cardiac sympathovagal imbalance, and cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) and nuclear factor ĸB (NF-κB) are involved in the development of IR-AS. Thus, we elucidated the pathological molecular mechanism of IR-AS by feeding an HFC diet to Tibetan minipigs to induce IR and AS. Methods Male Tibetan minipigs were fed either a normal diet or an HFC diet for 24 weeks. Thereafter, the minipigs were tested for physiological and biochemical blood indices, blood pressure, cardiac function, glucose tolerance, heart rate variability (HRV), and PPAR-associated gene and protein expression levels. Results HFC-fed minipigs exhibited IR through increased body weight, fasting blood glucose levels, plasma cholesterol and its composition, and insulin and free fatty acid (FFA) levels; decreased insulin sensitivity; impaired glucose tolerance; and hypertension. Increased C-reactive protein (CRP) levels, cardiac dysfunction, depressed HRV, and the up-regulation of PPAR expression in the abdominal aorta concomitant with down-regulation in the heart tissue were observed in HFC-fed minipigs. Furthermore, the levels of NF-κBp65, IL-1β, TNF-α, MCP-1, VCAM-1, ICAM-1, MMP-9, and CRP proteins were also significantly increased. Conclusions These data suggest that HFC-fed Tibetan minipigs develop IR and AS and that PPARs are involved in cardiovascular remodeling and impaired function.
Collapse
Affiliation(s)
- Pan Yongming
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Cai Zhaowei
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Ma Yichao
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Zhu Keyan
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Chen Liang
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Chen Fangming
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Xu Xiaoping
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Ma Quanxin
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| | - Chen Minli
- Experimental Animal Research Center, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China.
| |
Collapse
|
|
50
|
Chen TC, Sung ML, Kuo HC, Chien SJ, Yen CK, Chen CN. Differential regulation of human aortic smooth muscle cell proliferation by monocyte-derived macrophages from diabetic patients. PLoS One 2014; 9:e113752. [PMID: 25409512 PMCID: PMC4237499 DOI: 10.1371/journal.pone.0113752] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 10/28/2014] [Indexed: 11/18/2022] Open
Abstract
Macrophage accumulation in the arterial wall and smooth muscle cell (SMC) proliferation are features of type 2 diabetes mellitus (DM) and its vascular complications. However, the effects of diabetic monocyte-derived macrophages on vascular SMC proliferation are not clearly understood. In the present study, we investigated the pro-proliferative effect of macrophages isolated from DM patients on vascular SMCs. Macrophage-conditioned media (MCM) were prepared from macrophages isolated from DM patients. DM-MCM treatment induced HASMC proliferation, decreased p21(Cip1) and p27(Kip1) expressions, and increased microRNA (miR)-17-5p and miR-221 expressions. Inhibition of either miR-17-5p or miR-221 inhibited DM-MCM-induced cell proliferation. Inhibition of miR-17-5p abolished DM-MCM-induced p21(Cip1) down-regulation; and inhibition of miR-221 attenuated the DM-MCM-induced p27(Kip1) down-regulation. Furthermore, blocking assays demonstrated that PDGF-CC in DM-MCM is the major mediators of cell proliferation in SMCs. In conclusion, our present data support the hypothesis that SMC proliferation stimulated by macrophages may play critical roles in vascular complications in DM patients and suggest a new mechanism by which arterial disease is accelerated in diabetes.
Collapse
MESH Headings
- Adult
- Aorta/cytology
- Becaplermin
- Cell Proliferation/drug effects
- Cells, Cultured
- Culture Media, Conditioned/pharmacology
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Cyclin-Dependent Kinase Inhibitor p27/metabolism
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Down-Regulation/drug effects
- Enzyme-Linked Immunosorbent Assay
- Humans
- Lymphokines/analysis
- Macrophages/cytology
- Macrophages/immunology
- Macrophages/metabolism
- MicroRNAs/metabolism
- Middle Aged
- Monocytes/cytology
- Monocytes/immunology
- Monocytes/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Osteopontin/genetics
- Osteopontin/metabolism
- Platelet-Derived Growth Factor/analysis
- Proto-Oncogene Proteins c-sis/analysis
Collapse
Affiliation(s)
- Te-Chuan Chen
- Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mao-Ling Sung
- Department of Cardiology, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Hsing-Chun Kuo
- Institute of Nursing and Department of Nursing, Chang Gung University of Science and Technology, Chronic Diseases and Health Promotion Research Center, CGUST, Taoyuan, Taiwan
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Shao-Ju Chien
- Division of Pediatric Cardiology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chia-Kuang Yen
- Department of Cardiology, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Cheng-Nan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| |
Collapse
|