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Xu J, Wang H, Han B, Zhang X. Mechanisms through which laparoscopic sleeve gastrectomy mitigates atherosclerosis risk: a focus on visceral adipose tissue. Eur J Med Res 2025; 30:370. [PMID: 40336107 PMCID: PMC12057030 DOI: 10.1186/s40001-025-02635-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Bariatric surgery is currently considered the key treatment method for patients with obesity and related complications. Among the various surgeries, laparoscopic sleeve gastrectomy (LSG) is the most widely used. Obesity is a multifactor chronic disease characterized by the accumulation of visceral adipose tissue (VAT), leading to susceptibility to cardiac metabolic diseases. Many mechanisms, including abnormal lipid metabolism, insulin resistance, inflammation, endothelial dysfunction, adipocytokine imbalance and inflammasome activation, have been identified as the basis for the relationship between obesity and atherosclerosis. Bariatric surgery, such as LSG, reduces the risk of atherosclerosis in people living with obesity by reducing energy intake, disrupting energy balance and reducing the secretion of intestinal hormones to intervene in these risk factors. This review explores the current understanding of how LSG affects VAT and its impact on the risk of atherosclerosis.
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Affiliation(s)
- Juan Xu
- General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China.
| | - Heyue Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Bin Han
- Shanxi Provincial People's Hospital, Taiyuan, 030032, China
| | - Xiaomin Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
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Hernando-Redondo J, Toloba A, Benaiges D, Salas-Salvadó J, Martínez-Gonzalez MA, Corella D, Estruch R, Tinahones FJ, Ros E, Goday A, Castañer O, Fitó M. Mid- and long-term changes in satiety-related hormones, lipid and glucose metabolism, and inflammation after a Mediterranean diet intervention with the goal of losing weight: A randomized, clinical trial. Front Nutr 2022; 9:950900. [PMID: 36466401 PMCID: PMC9716624 DOI: 10.3389/fnut.2022.950900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/13/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Obesity is produced by the enlargement of the adipose tissue. Functioning as an endocrine organ, it releases and receives information through a complex network of cytokines, hormones, and substrates contributing to a low-chronic inflammation environment. Diet and healthy habits play key roles in the prevention of obesity and its related pathologies. In this regard, there is a need to switch to healthier and more appetizing diets, such as the Mediterranean one. OBJECTIVE To compare the mid-and long-term effects of two Mediterranean diet (MedDiet) interventions, one energy-reduced plus physical activity promotion versus a non-restrictive diet, on peripheral satiety-related hormones, weight loss, glucose/lipid metabolism, and pro-inflammatory markers in subjects with obesity/overweight and metabolic syndrome. MATERIALS AND METHODS A randomized, lifestyle intervention was conducted in 23 Spanish centers, with a large cohort of patients presenting metabolic syndrome. Our study is a subproject set in IMIM (Hospital del Mar Research Institute). Participants were men and women, aged 55-75 and 60-75, respectively, who at baseline met at least three metabolic syndrome components. Subjects were assigned to two intervention groups: (1) an intensive lifestyle intervention with an energy-reduced MedDiet and physical activity promotion (intervention group) with the aim of weight loss; and (2) a normocaloric MedDiet (control). We quantified in a subsample of 300 volunteers from Hospital del Mar Research Institute (Barcelona), following analytes at baseline, 6 months, and 1 year: glucose, HbA1c, triglycerides, total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, C-peptide, ghrelin, GLP-1, glucagon, insulin, leptin, PAI-1, resistin, and visfatin. Anthropometric and classical cardiovascular risk factors were also determined. A multivariate statistical model was employed to compare the two groups. Linear mixed-effect models were performed to compare changes in risk factors and biomarkers between intervention groups and over time. RESULTS Compared to participants in the control group, those in intervention one showed greater improvements in weight, waist circumference, insulin (P < 0.001), glucose metabolism-related compounds (P < 0.05), triglyceride-related lipid profile (P < 0.05), leptin, blood pressure, and pro-inflammatory markers such as PAI-1 (P < 0.001) at mid-and/or long-term. High-sensitivity C-reactive protein, resistin, and vifastin also decreased in both groups. CONCLUSION A weight loss intervention employing a hypocaloric MedDiet and physical activity promotion has beneficial effects on adiposity, glucose metabolism, lipid profile, leptin, and pro-inflammatory markers, such as PAI-1 in both mid-and long-term.
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Affiliation(s)
- J Hernando-Redondo
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
- Ph.D. Program in Food Science and Nutrition, Universitat de Barcelona, Barcelona, Spain
| | - A Toloba
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - D Benaiges
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
- Department of Endocrinology, Hospital Universitario del Mar, Barcelona, Spain
- Medicine Department and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - J Salas-Salvadó
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Unitat de Nutrició Humana, Reus, Spain
- Institut d’Investigació Pere Virgili, Hospital Universitari Sant Joan de Reus, Reus, Spain
| | - MA Martínez-Gonzalez
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - D Corella
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, Universidad de Valencia, Valencia, Spain
| | - R Estruch
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Internal Medicine Service, Hospital Clinic, Barcelona, Spain
| | - FJ Tinahones
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology, Biomedical Research Institute of Málaga, Virgen de la Victoria Hospital, University of Málaga (IBIMA), Málaga, Spain
| | - E Ros
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Department of Endocrinology and Nutrition, Lipid Clinic, IDIBAPS, Hospital Clínic, Barcelona, Spain
| | - A Goday
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
- Department of Endocrinology, Hospital Universitario del Mar, Barcelona, Spain
- Medicine Department and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - O Castañer
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - M Fitó
- Consorcio CIBER, Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute, Barcelona, Spain
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Ragino Y, Polonskaya Y, Spiridonov A, Striukova E, Shcherbakova L, Khudiakova A, Shramko V, Stakhneva E, Kashtanova E. Adipokines, Metabolic Hormones and Their Associations with Abdominal Obesity against a Background of Hyper-LDL-C in Young People. J Pers Med 2022; 12:jpm12111823. [PMID: 36579566 PMCID: PMC9698834 DOI: 10.3390/jpm12111823] [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: 10/04/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The present study was devoted to the search for possible associations between various adipokines/cytokines associated with the secretory activity of visceral adipocytes, elevated blood levels of LDL-C and abdominal obesity in people under 45 years. METHODS A population sample of Novosibirsk residents (n = 1415) was divided into deciles based on the levels of LDL-C. The study included 158 people, 87 men and 71 women, who had serum LDL-C levels of ≥4.2 mmol/L. Abdominal obesity was found in 50% of people (54% men, 45% women). By multiplex analysis using the human metabolic hormone V3 panel and the human adipokine magnetic bead panel, levels of adipokines and inflammatory markers were determined on a Luminex MAGPIX flow fluorimeter. RESULTS According to multivariate regression analysis (binary logistic regression), the most significant biomolecules, regardless of other factors, associated with the presence of AO against the background of hyper-LDL-C in young people were leptin (direct association) and lipocalin-2 (reverse association), leptin in young men (direct association), and leptin and TNF-alpha in women (direct association). CONCLUSIONS Thus, in young people under 45 years with the presence of two important, potentially atherogenic risk factors-hyper-LDL-C and abdominal obesity-a complex of adipokines and metabolic hormones were associated with the presence of these diseases.
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Hernandez V, Kaur K, ElSharief MW, Al Hajaj SW, Ebrahim AM, Razack M, Dragas D. The New Kid on the Block: The Mechanisms of Action of Hyperleptinemia in Coronary Artery Disease and Atherosclerosis. Cureus 2021; 13:e15766. [PMID: 34178553 PMCID: PMC8216571 DOI: 10.7759/cureus.15766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Leptin is an adipocytokine that consists of 167 amino acids. It functions as a regulator of hunger and energy expenditure. Leptin loses its ability to carry out its physiological function at high serum levels, and many studies have associated this loss of function with the development of coronary artery disease (CAD). This literature review aims to outline the steps by which leptin leads to CAD and atherosclerosis. Two independent researchers extracted animal and human studies from PubMed and Google Scholar databases. We applied PubMed search builder options: pathology, pathophysiology, metabolism, and physiology to focus the search results. This study concluded that the mechanism by which leptin might lead to CAD via pressor and depressor effects on vascular tone, enhancing atherosclerotic plaques, and through numerous single nucleotide polymorphisms, the most common being that of the leptin receptor gene rs113701.
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Affiliation(s)
- Vernicia Hernandez
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Kavaljeet Kaur
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohamed W ElSharief
- Pediatrics and Child Health, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sari W Al Hajaj
- Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ahmed M Ebrahim
- Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mirash Razack
- Emergency Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Wuhan University, Wuhan, CHN.,Internal Medicine, Al Ain Hospital, Al Ain, ARE
| | - David Dragas
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Thillan K, Lanerolle P, Thoradeniya T, Samaranayake D, Chandrajith R, Wickramasinghe P. Micronutrient status and associated factors of adiposity in primary school children with normal and high body fat in Colombo municipal area, Sri Lanka. BMC Pediatr 2021; 21:14. [PMID: 33407272 PMCID: PMC7786904 DOI: 10.1186/s12887-020-02473-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/15/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The prevalence of obesity and associated risk of chronic diseases are increasing among the paediatric population. The effectiveness of preventive measures and interventions are likely to improve when all factors which associate with obesity in a specific target group are considered. Currently such comprehensive data is unavailable for Sri Lankan children aged 8-9 years. METHODS This paper pertains to the data collected from August-2015 to November-2016 for a case-control study which included cases (high body fat) (N = 160; males-81) and controls (normal body fat) (N = 164; males-80) recruited from primary schools in the Colombo Municipal area. Anthropometry and body composition (Bioelectrical impedance analysis-BIA) were measured. Diet, physical activity and socio-demographic data were collected using validated interviewer administered questionnaires. Serum concentrations of vitamins A, D [25(OH)D], E, folate (serum and red blood cell-RBC), zinc (Zn), selenium (Se), copper (Cu), iron (Fe), magnesium (Mg), calcium (Ca), chromium (Cr), manganese (Mn), cobalt (Co), ferritin, leptin and high sensitivity C-reactive protein (hs-CRP) were assessed using fasting blood samples. RESULTS Cases were from higher socio-economic strata and spent significantly less time on physical activities, more time on sedentary behaviours and consumed higher energy compared to the controls. Cases from both genders had significantly lower levels of vitamin D [25 (OH)D], Fe and Mg (all p < 0.05) and higher levels of Cu and Ca (all p < 0.01) compared to controls. Higher levels of ferritin and Cr were seen among male (p < 0.001) and female (p > 0.05) cases compared to the controls. However, total serum folate levels were lower in male (p < 0.01) and female (p > 0.05) cases while the RBC folate levels were higher among male (p < 0.01) and female (p > 0.05) cases compared with controls. Vitamins A, E, Se, Mn and Co (p > 0.05) were not significantly different between groups. The inflammatory markers, both hs-CRP and leptin levels were higher among cases (p < 0.001) compared to the controls. CONCLUSIONS This study highlights higher socio-economic status, lower physical activity, more sedentary behaviours, higher energy intake and inconsistent distribution of micronutrients among the children with high body fat when compared with the control group. Increased levels of inflammatory markers indicate the presence of the risk of chronic inflammation in children with high body fat.
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Affiliation(s)
- Kalaichelvi Thillan
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Pulani Lanerolle
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Tharanga Thoradeniya
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Dulani Samaranayake
- Department of Community Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Rohana Chandrajith
- Department of Geology, Faculty of Science, University of Peradeniya, Peradeniya, Sri Lanka
| | - Pujitha Wickramasinghe
- Department of Paediatrics, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, Sri Lanka.
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Adipokines and Inflammation: Focus on Cardiovascular Diseases. Int J Mol Sci 2020; 21:ijms21207711. [PMID: 33081064 PMCID: PMC7589803 DOI: 10.3390/ijms21207711] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 02/08/2023] Open
Abstract
It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases.
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Feng Y, Kang K, Xue Q, Chen Y, Wang W, Cao J. Value of plasma homocysteine to predict stroke, cardiovascular diseases, and new-onset hypertension: A retrospective cohort study. Medicine (Baltimore) 2020; 99:e21541. [PMID: 32846763 PMCID: PMC7447408 DOI: 10.1097/md.0000000000021541] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The influences of hyperhomocysteinemia on cardiovascular diseases (CVDs), stroke and new-onset hypertension are unclear. The aim of the study is to explore the associations of homocysteine levels with stroke, CVDs, and new-onset hypertension in Chinese individuals.This retrospective cohort study included outpatients and inpatients from the Department of Geriatrics at Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine from January to December 2000. They were divided based on their homocysteine (Hcy) levels in 2000: Q1 (<10 μmol/L), Q2 (10-15 μmol/L), and Q3 (>15 μmol/L) and according to whether they had hypertension at baseline. Information about stroke, mortality and major adverse cardiac events, and newly onset hypertension was gathered in December each year until 2017. The effects of Hcy levels on the risk for stroke and CVDs among all patients, and new-onset hypertension among patients without hypertension at baseline were evaluated.After adjustment for confounders, compared with the Q1 group (Hcy <10 μmol/L), when the Hcy increased to 10 to 15 μmol/L, the risks for stroke, CVDs, and new-onset hypertension significantly increased, and the hazard ratio and 95% confidence interval were 2.02 (1.35-3.05, P = .001), 2.22 (1.32-3.76, P = .003), and 7.20 (4.52-11.48, P < .001), respectively. Hcy improved the predictive capability of traditional risk factors for stroke. The optimal cut-off value of Hcy for predicting stroke was 13.4 μmol/L (sensitivity: 70.9%, specificity: 62.2%).Hcy 10 to 15 μmol/L is significantly associated with the risks for stroke, mortality and major adverse cardiac events, and hypertension. The best cut-off point of Hcy for predicting stroke is 13.4 μmol/L.
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Ma L, Dai W, Lin Y, Zhang Z, Pan Y, Han H, Jia H, Peng J, Zhao J, Xu L. Leukocyte Rho kinase activity and serum cystatin C affect cardiovascular events in acute coronary syndrome. Medicine (Baltimore) 2020; 99:e20060. [PMID: 32664054 PMCID: PMC7360209 DOI: 10.1097/md.0000000000020060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE This study was designed to investigate the effects of leukocyte Rho kinase activity and serum Cystatin C (Cys C) on cardiovascular events in patients with acute coronary syndrome (ACS). METHODS A total of 48 patients with ST-segment elevation myocardial infarction (STEMI), 23 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 25 patients with unstable angina (UA) and 20 patients with no-acute coronary syndrome as control from January 2017 to June 2018 in Tianyou Hospital affiliated to Wuhan University of Science and Technology were selected in this study. Western blot was used to detect the leukocyte Rho kinase activity and Elisa kit was used to measure serum Cys C. Univariate and multivariate analysis were used to analyze the influencing factors of cardiovascular events in ACS patients. RESULTS The activity of leukocyte Rho kinase and serum Cys C were gradually reduced in the STEMI, NSTEMI and UA patients, but all significantly higher than that in No-ASC patients, and there was a positive correlation between leukocyte Rho kinase activity and serum Cys C in ACS patients (r = 0.516, P < .001). The activity of leukocyte Rho kinase was positively correlated with the levels of serum TNF-α (r = 0.634, P < .001), IL-6 (r = 0.578, P < .001), IL-8 (r = 0.582, P < .001) in ACS patients, and the level of Cys C was positively correlated with the levels of serum TNF-α (r = 0.634, P < .001), IL-6 (r = 0.578, P < .001), IL-8 (r = 0.582, P < .001) in ACS patients. Univariate and multivariate analysis showed that the leukocyte Rho kinase activity (HR = 2.994, 95%CI = 1.328-6.054, P < .0001) and the levels of serum Cys C (HR = 1.692, 95%CI = 1.028-2.124, P < .0001) were independent influencing factors of cardiovascular events in ACS patients. CONCLUSION The leukocyte Rho kinase activity and serum Cystatin C are high in acute coronary syndrome patients, and are the independent influencing factors of cardiovascular events in ACS patients.
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Affiliation(s)
- Li Ma
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Wenqin Dai
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
- Department of Cardiology, Wuchang Hospital of Wuhan
| | - Yongbo Lin
- Department of Cardiology, People's Hospital of Dongxihu
| | - Zhongyuan Zhang
- Department of Pharmacy, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Yunhong Pan
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Hongyan Han
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Haizhen Jia
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Jun Peng
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Jinhe Zhao
- Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science and Technology
| | - Liang Xu
- Department of Intensive Care Unit, WuHan, China
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Tseng CH, Chung WJ, Li CY, Tsai TH, Lee CH, Hsueh SK, Wu CC, Cheng CI. Statins reduce new-onset atrial fibrillation after acute myocardial infarction: A nationwide study. Medicine (Baltimore) 2020; 99:e18517. [PMID: 31914024 PMCID: PMC6959943 DOI: 10.1097/md.0000000000018517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Atrial fibrillation (AF) is an important complication of acute myocardial infarction (AMI). The association between AF and serum lipid profile is unclear and statin use for lowering the incidence of new-onset AF remains controversial. The objective of this study was to investigate whether statins confer a beneficial effect on AF after AMI.Data available in the Taiwan National Health Insurance Research Database on 32886 AMI patients between 2008 and 2011 were retrospectively analyzed. Total 27553 (83.8%) had complete 1-yr follow-up data. Cardiovascular outcomes were analyzed based on the baseline characteristics and AF type (existing, new-onset, or non-AF). AF groups had significantly higher incidence of heart failure (HF), stroke, all-cause death, and major adverse cardiac and cerebrovascular event (MACCE) after index AMI (all P < .05). In contrast, myocardial re-infarction (re-MI) was not significantly different among the three groups (P = .95). Statin use tended to be associated with lower risk of new-onset AF after AMI (HR: 0.935; 95% confidence interval (CI): 0.877-0.998; P = .0427).Existing AF and new-onset AF subgroups had similar cardiovascular outcomes after AMI and were both inferior to the non-AF group. Statin tended to reduce new-onset AF after AMI.
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Affiliation(s)
- Chien-Hao Tseng
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Wen-Jung Chung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Chen-Yu Li
- Clinical Informatics and Medical Statistics Research Center, Taiwan, ROC
- Foreign Language and International Trade School, Wenzhou Business College, Wenzhou, China
| | - Tzu-Hsien Tsai
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Chien-Ho Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Shu-Kai Hsueh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Chia-Chen Wu
- Division of Cardiothoracic and Vascular Surgery, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
| | - Cheng-I Cheng
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung
- Chang Gung University College of Medicine, Guishan District, Taoyuan City, Taiwan, ROC
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Sabatino J, Wicik Z, De Rosa S, Eyileten C, Jakubik D, Spaccarotella C, Mongiardo A, Postula M, Indolfi C. MicroRNAs fingerprint of bicuspid aortic valve. J Mol Cell Cardiol 2019; 134:98-106. [DOI: 10.1016/j.yjmcc.2019.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/17/2019] [Accepted: 07/01/2019] [Indexed: 02/07/2023]
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Role of microRNA-15a-5p in the atherosclerotic inflammatory response and arterial injury improvement of diabetic by targeting FASN. Biosci Rep 2019; 39:BSR20181852. [PMID: 31182467 PMCID: PMC6603278 DOI: 10.1042/bsr20181852] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 04/10/2019] [Accepted: 05/31/2019] [Indexed: 12/17/2022] Open
Abstract
The present study aims to investigate the mechanism of miR-15a-5p in the atherosclerotic (AS) inflammatory response and arterial injury improvement in diabetic rats by regulating fatty acid synthase (FASN). Initially, bioinformatics tools were applied to evaluate miRNAs and genes correlating with AS, and the target relation between miRNAs and FASN was measured using the Dual-Luciferase Reporter Assay. Subsequently the diabetic AS rat model was established and the surviving rats were divided into: negative control (NC), miR-15a-5p mimic, miR-15a-5p inhibitor, sh-FASN and miR-15a-5p + sh-FASN groups. Then a series of experiments were performed to examine the degree of AS in each group. The results revealed that compared with the NC group, the expressions of C-reactive protein (CRP), interleukin 6 (IL-6), intercellular cell adhesion molecule-1 (ICAM1) in rat arterial tissue, as well as the levels of low-density lipoprotein cholesterol (LDL-C), blood glucose (BG), triglycerides (TG), total cholesterol (TC) and Homocysteine (Hcy) in rat serum, were increased after inhibiting miR-15a-5p, while the level of high-density lipoprotein cholesterol (HDL-C) was decreased and the fat storage area was enlarged after this treatment (P<0.05). In the miR-15a-5p mimic and sh-FASN groups, serum HDL-C levels were increased and the fat storage areas in arteries were reduced. The levels of CRP, IL-6, ICAM1 in rat arterial tissue, along with the levels of LDL-C, BG, TG, TC and Hcy in rat serum, were decreased (P<0.05). Hematoxylin and Eosin (HE) staining and transmission electron microscopy (TEM) results showed AS lesions to be apparent in the arteries of rats in both the NC and miR-15a-5p inhibitor groups, but that in miR-15a-5p and sh-FASN group were improved, the miR-15a-5p mimic + sh-FASN group showed the most obvious improvement. Taken together, miR-15a-5p alleviates the inflammation response and arterial injury in diabetic AS rats by targeting FASN.
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Grittani M, Pellegrino G, Conte S, Morello A, Autore A, Cimmino G, Trimarco B, Morgagni F, Cirillo P. Effects of Hypobaric Hypoxia on Endothelial Function and Adiponectin Levels in Airforce Aviators. High Alt Med Biol 2019; 20:165-170. [PMID: 31161940 DOI: 10.1089/ham.2018.0128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: Hypobaric hypoxia (HH) increases the risk of high altitude-related illnesses (HARI). The pathophysiological mechanism(s) involved are still partially unknown. Altered vascular reactivity as consequence of endothelial dysfunction during HH might play a role in this phenomenon. Adiponectin exerts protective effect on cardiovascular system since it modulates NO release, antagonizing endothelial dysfunction. Aims of this study, performed in a selected population of airforce aviators, were (1) to investigate whether exposure to acute HH might be associated with endothelial dysfunction and (2) to evaluate whether adiponectin might be involved in modulating this phenomenon. Methods: Twenty aviators were exposed to acute HH in a hypobaric chamber by simulating altitude of 8000 and then 6000 m for 2 hours. Vascular reactivity was evaluated by the EndoPAT test immediately before and after the HH; salivary and blood adiponectin levels were measured. Results: EndoPAT performed immediately after HH divided pilots in two groups: 12 pilots with preserved vascular reactivity and 8 pilots with reduction of vascular reactivity, indicating that HH exposure might cause endothelial dysfunction. Salivary and blood adiponectin levels increased post-HH in a time-dependent manner in all aviators, but the significant increase was observed only in those with preserved vascular reactivity suggesting that HH stimulated release of adiponectin that, in turn, by exerting a protective effect, might reduce endothelial dysfunction. Conclusions: Acute HH may cause endothelial dysfunction due, at least in part, to reduced release of adiponectin. This phenomenon might be involved in pathophysiology of HARI.
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Affiliation(s)
| | - Grazia Pellegrino
- 2 Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Stefano Conte
- 3 Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples "Federico II," Naples, Italy
| | - Andrea Morello
- 3 Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples "Federico II," Naples, Italy
| | - Alberto Autore
- 4 Aerospace Medicine Department, Flight Experimental Centre, Italian Airforce, Rome, Italy
| | - Giovanni Cimmino
- 2 Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Bruno Trimarco
- 3 Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples "Federico II," Naples, Italy
| | - Fabio Morgagni
- 5 Aerospace Medicine Institute "Aldo Di Loreto," Rome, Italy
| | - Plinio Cirillo
- 3 Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples "Federico II," Naples, Italy
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Adela R, Reddy PNC, Ghosh TS, Aggarwal S, Yadav AK, Das B, Banerjee SK. Serum protein signature of coronary artery disease in type 2 diabetes mellitus. J Transl Med 2019; 17:17. [PMID: 30674322 PMCID: PMC6345069 DOI: 10.1186/s12967-018-1755-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 12/21/2018] [Indexed: 12/11/2022] Open
Abstract
Background Coronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The purpose of the present study was to discriminate the Indian CAD patients with or without T2DM by using multiple pathophysiological biomarkers. Methods Using sensitive multiplex protein assays, we assessed 46 protein markers including cytokines/chemokines, metabolic hormones, adipokines and apolipoproteins for evaluating different pathophysiological conditions of control, T2DM, CAD and T2DM with CAD patients (T2DM_CAD). Network analysis was performed to create protein-protein interaction networks by using significantly (p < 0.05) altered protein markers in each disease using STRING 10.5 database. We used two supervised analysis methods i.e., between class analysis (BCA) and principal component analysis (PCA) to reveals distinct biomarkers profiles. Further, random forest classification (RF) was used to classify the diseases by the panel of markers. Results Our two supervised analysis methods BCA and PCA revealed a distinct biomarker profiles and high degree of variability in the marker profiles for T2DM_CAD and CAD. Thereafter, the present study identified multiple potential biomarkers to differentiate T2DM, CAD, and T2DM_CAD patients based on their relative abundance in serum. RF classified T2DM based on the abundance patterns of nine markers i.e., IL-1β, GM-CSF, glucagon, PAI-I, rantes, IP-10, resistin, GIP and Apo-B; CAD by 14 markers i.e., resistin, PDGF-BB, PAI-1, lipocalin-2, leptin, IL-13, eotaxin, GM-CSF, Apo-E, ghrelin, adipsin, GIP, Apo-CII and IP-10; and T2DM _CAD by 12 markers i.e., insulin, resistin, PAI-1, adiponectin, lipocalin-2, GM-CSF, adipsin, leptin, Apo-AII, rantes, IL-6 and ghrelin with respect to the control subjects. Using network analysis, we have identified several cellular network proteins like PTPN1, AKT1, INSR, LEPR, IRS1, IRS2, IL1R2, IL6R, PCSK9 and MYD88, which are responsible for regulating inflammation, insulin resistance, and atherosclerosis. Conclusion We have identified three distinct sets of serum markers for diabetes, CAD and diabetes associated with CAD in Indian patients using nonparametric-based machine learning approach. These multiple marker classifiers may be useful for monitoring progression from a healthy person to T2DM and T2DM to T2DM_CAD. However, these findings need to be further confirmed in the future studies with large number of samples. Electronic supplementary material The online version of this article (10.1186/s12967-018-1755-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ramu Adela
- Drug Discovery Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India.,Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, NIPER, Guwahati, Assam, India
| | | | - Tarini Shankar Ghosh
- Centre for Human Microbial Ecology, Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Suruchi Aggarwal
- Drug Discovery Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Amit Kumar Yadav
- Drug Discovery Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Bhabatosh Das
- Centre for Human Microbial Ecology, Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Sanjay K Banerjee
- Drug Discovery Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India.
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MicroRNAs as Diagnostic and Prognostic Biomarkers in Ischemic Stroke-A Comprehensive Review and Bioinformatic Analysis. Cells 2018; 7:cells7120249. [PMID: 30563269 PMCID: PMC6316722 DOI: 10.3390/cells7120249] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/01/2018] [Accepted: 12/02/2018] [Indexed: 12/14/2022] Open
Abstract
Stroke is the second-most common cause of death worldwide. The pathophysiology of ischemic stroke (IS) is related to inflammation, atherosclerosis, blood coagulation, and platelet activation. MicroRNAs (miRNAs) play important roles in physiological and pathological processes of neurodegenerative diseases and progression of certain neurological diseases, such as IS. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of IS. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique value as diagnostic and prognostic markers in IS. In this review, we focus on the role of miRNAs as diagnostic and prognostic biomarkers in IS. We discuss the most common and reliable detection methods available and promising tests currently under development. We also present original results from bioinformatic analyses of published results, identifying the ten most significant genes (HMGB1, YWHAZ, PIK3R1, STAT3, MAPK1, CBX5, CAPZB, THBS1, TNFRSF10B, RCOR1) associated with inflammation, blood coagulation, and platelet activation and targeted by miRNAs in IS. Additionally, we created miRNA-gene target interaction networks based on Gene Ontology (GO) information derived from publicly available databases. Among our most interesting findings, miR-19a-3p is the most widely modulated miRNA across all selected ontologies and might be proposed as novel biomarker in IS to be tested in future studies.
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Jia Y, Li D, Cao Y, Cheng Y, Xiao L, Gao Y, Zhang L, Zeng Z, Wan Z, Zeng R. Inflammation-based Glasgow Prognostic Score in patients with acute ST-segment elevation myocardial infarction: A prospective cohort study. Medicine (Baltimore) 2018; 97:e13615. [PMID: 30558040 PMCID: PMC6319978 DOI: 10.1097/md.0000000000013615] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 11/16/2018] [Indexed: 02/05/2023] Open
Abstract
The inflammation-based Glasgow Prognostic Score (GPS), which involves C-reactive protein and serum albumin levels, has been reported to be a strong independent predictor of mortality in many cancers. This study aimed to investigate whether the GPS is associated with mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI).In this study, 406 consecutive patients with STEMI at our emergency department (ED) who were undergoing pPCI were prospectively enrolled and assigned a GPS of 0, 1, or 2. Kaplan-Meier survival and multivariable Cox regression analyses were used to evaluate the associations between the GPS and long-term mortality.Twenty-three patients (5.7%) died at the hospital, and 37 (9.7%) died during follow-up (14.4 [9.3-17.6] months). Compared with patients with a lower GPS, those with a higher GPS had significantly higher in-hospital mortality (GPS = 0 vs GPS = 1 vs GPS = 2: 3.3% vs 6.3% vs 28.0%, P < .001), follow-up mortality (4.6% vs 14.3% vs 55.6%, P < .001), and cumulative mortality (9.6% vs 21.1% vs 71.1%, P < .001). Multivariable Cox regression analysis revealed that in patients with a GPS of 1 and 2 (versus 0), the multivariable adjusted hazard ratios (HR) for all-cause mortality were 2.068 (95% CI: 1.082-3.951, P = .028) and 8.305 (95% CI: 4.017-17.171, P < .001), respectively, after controlling for all of the confounding factors. Subgroup analysis showed that a higher GPS was associated with an increased risk of cumulative mortality in the different subgroups.The GPS on admission may be useful for stratifying the risk of adverse outcomes in patients with STEMI undergoing pPCI in the ED.
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Affiliation(s)
- Yu Jia
- Department of Emergency Medicine, West China Hospital
- Disaster Medicine Center
- Laboratory of Emergency Medicine
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Dongze Li
- Department of Emergency Medicine, West China Hospital
- Disaster Medicine Center
- Laboratory of Emergency Medicine
| | - Yu Cao
- Department of Emergency Medicine, West China Hospital
- Disaster Medicine Center
- Laboratory of Emergency Medicine
| | - Yisong Cheng
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Xiao
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongli Gao
- Department of Emergency Medicine, West China Hospital
- Disaster Medicine Center
- Laboratory of Emergency Medicine
| | - Lin Zhang
- Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Hong Kong, China
| | - Zhi Zeng
- Department of Emergency Medicine, West China Hospital
| | - Zhi Wan
- Department of Emergency Medicine, West China Hospital
- Disaster Medicine Center
- Laboratory of Emergency Medicine
| | - Rui Zeng
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
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Zhang J, Jin J, Liu J, He Y, Zhang P, Ye W, Zhu W, Li M. A study of the correlation of insulin resistance and leptin with inflammatory factors and vascular endothelial injury in T2DM patients with CHD. Exp Ther Med 2018; 16:265-269. [PMID: 29896248 PMCID: PMC5995089 DOI: 10.3892/etm.2018.6170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 04/17/2018] [Indexed: 12/18/2022] Open
Abstract
The purpose of this study was to explore the correlation of insulin resistance (IR) and leptin with inflammatory factors and vascular endothelial injury in patients with type 2 diabetes mellitus (T2DM) complicated with coronary heart disease (CHD) was explored. One hundred and fifty normal patients (normal group), 150 patients with pure T2DM (T2DM group) and 150 patients with T2DM complicated with coronary heart disease (T2DM + CHD group) were selected from Xi'an No. 5 Hospital. All the participants met our inclusion criteria. Age, body mass index, waist-to-hip ratio, blood lipid and fasting plasma glucose (FPG), of all the subjects were measured. Chemiluminescent immunoassay was adopted for the detection of FPG and double-antibody sandwich method was used for the determination of fasting plasma leptin, and assay of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Insulin resistance index (IRI) was used to evaluate IR and enzyme-linked immunosorbent assay was adopted for the detection of von Willebrand factor (vWF) and endothelin (ET-1). Compared with the control group, patients in the T2DM + CHD group and those in the T2DM group had higher homeostasis model assessment-IR, and higher assay of plasma leptin, hs-CRP, IL-6 and TNF-α (P<0.05), and lower vascular endothelial function (P<0.05). Moreover, compared with the T2DM group, T2DM + CHD group had higher plasma leptin, and higher assay of hs-CRP, IL-6 and TNF-α (P<0.05). IRI was positively correlated with hs-CRP (r=0.521, P=0.001), IL-6 (r=0.359, P=0.001) and TNF-α (r=0.386, P=0.001), leptin was positively correlated with hs-CRP (r=0.305, P=0.001), IL-6 (r=0.259, P=0.002) and TNF-α (r=0.429, P=0.001), and IRI had no correlation with ET-1 (r=0.058, P=0.734) and vWF (r=0.047, P=0.812), that is, it had no direct correlation with vascular endothelial function. Level of leptin was positively correlated with ET-1 (r=0.366, P=0.001) and vWF (r=0.471, P=0.001), that is, it was negatively correlated with vascular endothelial function. Our results showed that leptin, hs-CRP, IL-6 and TNF-α are involved in the occurrence and development of CHD in patients with T2DM. IR has no direct correlation with the occurrence and development of CHD in patients with T2DM.
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Affiliation(s)
- Jie Zhang
- Department of Cardiology, Xi'an No. 5 Hospital, Xi'an, Shaanxi 710082, P.R. China
| | - Jing Jin
- Department of Geriatrics, Xi'an No. 5 Hospital, Xi'an, Shaanxi 710082, P.R. China
| | - Jilun Liu
- Department of Cardiology, No. 215 Hospital of Shaanxi Nuclear Industry, Xianyang, Shaanxi 712000, P.R. China
| | - Yajun He
- Department of Cardiology, No. 215 Hospital of Shaanxi Nuclear Industry, Xianyang, Shaanxi 712000, P.R. China
| | - Peng Zhang
- Department of Cardiology, The Affiliated Hospital of Yan'an University, Yan'an, Shaanxi 716000, P.R. China
| | - Wucheng Ye
- Department of Cardiology, Xingyuan Hospital of Yulin, Yulin, Shaanxi 719000, P.R. China
| | - Wei Zhu
- Department of Clinical Laboratory, The Central Hospital of Baoji, Baoji, Shaanxi 721008, P.R. China
| | - Mingliang Li
- Department of Cardiovascular Medicine, Hanzhong People's Hospital, Hanzhong, Shaanxi 723000, P.R. China
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Cimmino G, Loffredo FS, Morello A, D'Elia S, De Palma R, Cirillo P, Golino P. Immune-Inflammatory Activation in Acute Coronary Syndromes: A Look into the Heart of Unstable Coronary Plaque. Curr Cardiol Rev 2017; 13:110-117. [PMID: 27758696 PMCID: PMC5452145 DOI: 10.2174/1573403x12666161014093812] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/24/2016] [Accepted: 10/06/2016] [Indexed: 12/21/2022] Open
Abstract
In the last twenty years, our comprehension of the molecular mechanisms involved in the formation, progression and complication of atherosclerotic plaque has advanced significantly and the main role of inflammation and immunity in this phenomenon is now largely accepted. Accumulating evidence highlight the crucial role of different inflammatory and immune cells, such as monocytes and T-lymphocytes, in the pathophysiology of atherosclerotic lesion, particularly in contributing to its com-plications, such as rupture or ulceration. According to the new terminology, “vulnerable plaque” identi-fies an inflamed atherosclerotic lesion that is particularly prone to rupture. Once disrupted, prothrom-botic material is exposed to the flowing blood, thus activating coagulation cascade and platelet aggrega-tion, ultimately leading to acute thrombus formation within the coronary vessel. To date this is the key event underlying the clinical manifestations of acute coronary syndromes (ACS). The degree of vessel occlusion (complete vs. incomplete) and the time of blood flow cessation will define the severity of clinical picture. This phenomenon seems to be the final effect of a complex inter-action between different local and systemic factors, involving the degree of inflammation, type of cells infiltration and the rheological characteristics of blood flow at the site of plaque rupture, thrombogenic substrates within the atherosclerotic lesion and different soluble mediators, already present or acutely released in the circulating blood. This article will review currently available data on the pathophysiology of ACS, emphasizing the immunological and inflammatory aspects of vulnerable plaque. We may pos-tulate that intraplaque antigens and local microenvironment will define the immune-inflammatory re-sponse and cells phenotype, thus determining the severity of clinical manifestations.
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Affiliation(s)
- Giovanni Cimmino
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, Second University of Naples, Naples, Italy
| | - Francesco S Loffredo
- Molecular Cardiology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Alberto Morello
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, Second University of Naples, Naples, Italy
| | - Saverio D'Elia
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, Second University of Naples, Naples, Italy
| | - Raffaele De Palma
- Department of Clinical and Experimental Medicine, Section of Immunology, Second University of Naples, Naples, Italy
| | - Plinio Cirillo
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Paolo Golino
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, Second University of Naples, Naples, Italy
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El husseny MWA, Mamdouh M, Shaban S, Ibrahim Abushouk A, Zaki MMM, Ahmed OM, Abdel-Daim MM. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity. J Diabetes Res 2017; 2017:8095926. [PMID: 28286779 PMCID: PMC5327767 DOI: 10.1155/2017/8095926] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/16/2017] [Indexed: 12/20/2022] Open
Abstract
Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP) and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM), insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity.
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Affiliation(s)
- Mostafa Wanees Ahmed El husseny
- Faculty of Medicine, Fayoum University, Fayoum, Egypt
- NovaMed Medical Research Association, Cairo, Egypt
- Fayoum Medical Student Association, Fayoum, Egypt
| | | | - Sara Shaban
- Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | | | | | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed M. Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
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Cimmino G, Ciuffreda LP, Ciccarelli G, Calabrò P, Ferraiolo FAV, Rivellino A, De Palma R, Golino P, Rossi F, Cirillo P, Berrino L. Upregulation of TH/IL-17 Pathway-Related Genes in Human Coronary Endothelial Cells Stimulated with Serum of Patients with Acute Coronary Syndromes. Front Cardiovasc Med 2017; 4:1. [PMID: 28224128 PMCID: PMC5293806 DOI: 10.3389/fcvm.2017.00001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/11/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammation plays an essential role in the development and complications of atherosclerosis plaques, including acute coronary syndromes (ACS). Indeed, previous reports have shown that within the coronary circulation of ACS patients, several soluble mediators are released. Moreover, it has been demonstrated that endothelial dysfunction might play an important role in atherosclerosis as well as ACS pathophysiology. However, the mechanisms by which these soluble mediators might affect endothelial functions are still largely unknown. We have evaluated whether soluble mediators contained in serum from coronary circulation of ACS patients might promote changes of gene profile in human coronary endothelial cells (HCAECs). METHODS HCAECs were stimulated in vitro for 12 h with serum obtained from the coronary sinus (CS) and the aorta (Ao) of ACS patients; stable angina (SA) patients served as controls. Gene expression profiles of stimulated cells were evaluated by microarray and real-time PCR. RESULTS HCAECs stimulated with serum from CS of ACS patients showed a significant change (upregulation and downregulation) in gene expression profile as compared with cells stimulated with serum from CS of SA patients. Moreover, ad hoc sub analysis indicated the upregulation of Th-17/IL-17 pathway-related genes. CONCLUSION This study demonstrates that, in ACS patients, the chemical mediators released in the coronary circulation might be able to perturb coronary endothelial cells (ECs) modifying their gene profile. These modified ECs, through downregulation of protective gene and, mainly, through upregulation of gene able to modulate the Th-17/IL-17 pathway, might play a key role in progression of coronary atherosclerosis and in developing future acute events.
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Affiliation(s)
- Giovanni Cimmino
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Loreta Pia Ciuffreda
- Department of Experimental Medicine, Section of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giovanni Ciccarelli
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Paolo Calabrò
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | | | - Alessia Rivellino
- Department of Experimental Medicine, Section of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Raffaele De Palma
- Department of Clinical and Experimental Medicine, Section of Immunology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Paolo Golino
- Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, Section of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Plinio Cirillo
- Department of Advanced Biomedical Sciences, Section of Cardiology, University of Naples, “Federico II”, Naples, Italy
| | - Liberato Berrino
- Department of Experimental Medicine, Section of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy
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Human C-reactive protein impedes entry of leptin into the CNS and attenuates its physiological actions in the CNS. Biochem J 2016; 473:1215-24. [DOI: 10.1042/bj20151282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 03/01/2016] [Indexed: 01/08/2023]
Abstract
Defective central leptin signalling and impaired leptin entry into the CNS (central nervous system) represent two important aspects of leptin resistance in obesity. In the present study, we tested whether circulating human CRP (C-reactive protein) not only diminishes signalling of leptin within the CNS, but also impedes this adipokine's access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore, following peripheral infusion of human leptin, the CSF (cerebrospinal fluid) concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS (lipopolysaccharide) to human CRP-transgenic mice dramatically elevated the concentrations of human CRP in the CSF. The i.c.v. (intracerebroventricular) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signalling by human leptin, and ameliorated the effects of leptin on the expression of NPY (neuropeptide Y), AgRP (Agouti-related protein), POMC (pro-opiomelanocortin) and SOCS-3 (suppressor of cytokine signalling 3). Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin.
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Maresca F, Di Palma V, Bevilacqua M, Uccello G, Taglialatela V, Giaquinto A, Esposito G, Trimarco B, Cirillo P. Adipokines, vascular wall, and cardiovascular disease: a focused overview of the role of adipokines in the pathophysiology of cardiovascular disease. Angiology 2015; 66:8-24. [PMID: 24535638 DOI: 10.1177/0003319713520463] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Epidemiological evidence has shown that abdominal obesity is closely associated with the development of cardiovascular (CV) disease, suggesting that it might be considered as an independent CV risk factor. However, the pathophysiological mechanisms responsible for the association between these 2 clinical entities remain largely unknown. Adipocytes are considered able to produce and secrete chemical mediators known as "adipokines" that may exert several biological actions, including those on heart and vessels. Of interest, a different adipokine profile can be observed in the plasma of patients with obesity or metabolic syndrome compared with healthy controls. We consider the main adipokines, focusing on their effects on the vascular wall and analyzing their role in CV pathophysiology.
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Affiliation(s)
- Fabio Maresca
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Vito Di Palma
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Michele Bevilacqua
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Giuseppe Uccello
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Vittorio Taglialatela
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Alessandro Giaquinto
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Giovanni Esposito
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
| | - Plinio Cirillo
- Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples, Naples, Italy
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Hribal ML, Fiorentino TV, Sesti G. Role of C reactive protein (CRP) in leptin resistance. Curr Pharm Des 2014; 20:609-15. [PMID: 23688010 PMCID: PMC4155811 DOI: 10.2174/13816128113199990016] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 05/13/2013] [Indexed: 01/23/2023]
Abstract
Increased plasma levels of both leptin and C reactive protein (CRP) have been reported in a number of conditions, including obesity, and have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk; interestingly these two biomarkers appear to be able to reciprocally regulate their bioavailability, through complex mechanisms that have not been completely clarified yet. Here we first review clinical evidence suggesting not only that the circulatory levels of CRP and leptin show an independent correlation, but also that assessing them in tandem may result in an increased ability to predict cardiovascular disease. We summarize also molecular studies showing that leptin is able to promote CRP production from hepatocytes and endothelial cells in vitro and discuss the studies addressing the possibility that in vivo leptin administration may be able to modulate plasma CRP levels. Furthermore, we describe two studies demonstrating that CRP directly binds leptin in extra-cellular settings, thus impairing its biological actions. Finally we report genetic evidence that common variations at the leptin receptor locus are associated with CRP blood levels. Overall, the data reviewed here show that the chronic elevation of CRP observed in obese subjects may worsen leptin resistance, contributing to the pathogenesis of cardiovascular disease, and highlight a potential link between conditions, such as leptin resistance and endothelial dysfunction, that may be amenable of pharmacological treatment targeted to the disruption of leptin-CRP interaction.
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Affiliation(s)
| | | | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University of Catanzaro Magna Graecia, Viale Europa, località Germaneto 88100 Catanzaro, Italy.
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Cimmino G, Conte S, Morello A, D’Elia S, Marchese V, Golino P. The complex puzzle underlying the pathophysiology of acute coronary syndromes: from molecular basis to clinical manifestations. Expert Rev Cardiovasc Ther 2014; 10:1533-43. [DOI: 10.1586/erc.12.157] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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24
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Cimmino G, Ragni M, Cirillo P, Petrillo G, Loffredo F, Chiariello M, Gresele P, Falcinelli E, Golino P. C-reactive protein induces expression of matrix metalloproteinase-9: a possible link between inflammation and plaque rupture. Int J Cardiol 2013; 168:981-986. [PMID: 23157807 DOI: 10.1016/j.ijcard.2012.10.040] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 10/04/2012] [Accepted: 10/28/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of acute coronary syndromes (ACS). However, little is known about the mechanisms responsible for MMP expression in ACS. C-reactive protein (CRP) not only is an independent risk factor for cardiovascular events, but also may exert direct pro-atherosclerotic effects. Therefore, we aimed at determining whether CRP might induce MMP-9 in two different experimental conditions: 1) smooth muscle cells (SMCs) in vitro, and 2) patients with ACS. METHODS AND RESULTS Effects of increasing concentrations of CRP on MMP-9 expression were evaluated in vitro in human SMCs. TIMP-1 protein expression, the selective inhibitor of MMP-9, was also evaluated. CRP dose-dependently induced MMP-9 expression in SMCs by promoting MMP-mRNA transcription, as well as MMP-9 secretion. In contrast, no differences were found for TIMP-1 protein expression. In vivo, MMP-9 and CRP levels were measured in blood samples obtained from the aorta (Ao) and the coronary sinus (Cs) of patients with normal coronary arteries (controls, n=21), stable angina (n=24), and ACS (n=30). Both MMP-9 and CRP plasma levels were significantly increased across the coronary circulation only in patients with ACS. Interestingly, a significant correlation between MMP-9 and CRP plasma levels was found. CONCLUSIONS CRP induced MMP-9 expression and activity in human SMCs in culture; patients presenting with ACS have increased transcoronary plasma levels of MMP-9 and CRP with a significant correlation between these two markers. This may explain the heightened risk of coronary events in subjects with elevated levels of CRP.
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MESH Headings
- Acute Coronary Syndrome/enzymology
- Acute Coronary Syndrome/genetics
- Acute Coronary Syndrome/metabolism
- Aged
- C-Reactive Protein/metabolism
- C-Reactive Protein/physiology
- Cells, Cultured
- Female
- Gene Expression Regulation, Enzymologic
- Humans
- Inflammation/enzymology
- Inflammation/genetics
- Inflammation/metabolism
- Male
- Matrix Metalloproteinase 9/biosynthesis
- Matrix Metalloproteinase 9/genetics
- Middle Aged
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Plaque, Atherosclerotic/blood
- Plaque, Atherosclerotic/enzymology
- Plaque, Atherosclerotic/metabolism
- Up-Regulation/genetics
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Affiliation(s)
- Giovanni Cimmino
- Department of Cardiothoracic and Respiratory Sciences, Division of Cardiology, Second University of Naples, Naples, Italy
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25
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Misiak B, Leszek J, Kiejna A. Metabolic syndrome, mild cognitive impairment and Alzheimer's disease--the emerging role of systemic low-grade inflammation and adiposity. Brain Res Bull 2012; 89:144-9. [PMID: 22921944 DOI: 10.1016/j.brainresbull.2012.08.003] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 07/22/2012] [Accepted: 08/08/2012] [Indexed: 01/16/2023]
Abstract
The past decade has shed new light on the etiology of Alzheimer's disease (AD), which is the consequence of interactions between numerous lesions. There is a growing body of evidence that the most beneficial effects of treatment might only be achieved in the preclinical stage of dementia, prior to the immense hallmarks of neurodegeneration. In view of this, several studies have focused on mild cognitive impairment (MCI) as a state, which represents a less severe form of the neuropathological process. However, early treatment interventions initiated in MCI have failed to slow down progression of the disease. Thus, great effort has been made to indicate modifiable risk factors for MCI. Consistent with the role of vascular malfunction in AD, this approach has shown the predictive value of the metabolic syndrome (MetS), which is a multidimensional entity and includes visceral obesity, dyslipidemia, hyperglycemia and hypertension. Despite the positive results of several epidemiological studies, the exact mechanisms underlying the connection between MetS and AD remain uncertain and various theories are being assessed. MetS, similarly to AD, has been attributed to a low-grade chronic inflammation. There is a general consensus that the aberrant inflammatory response underlying MetS may arise from a deregulation of the endocrine homeostasis of adipose tissue. Hence, it might be assumed that the subclinical inflammation of adipose tissue may interact with the impaired central inflammatory response, leading to neurodegeneration. This article reviews the role of low-grade inflammation of adipose tissue in the pathophysiology of cognitive impairment and translates several considerable and unexplored findings from studies focused on subjects with MetS and animal models mimicking the phenotype of MetS into the etiology of AD.
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Affiliation(s)
- Blazej Misiak
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland.
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26
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Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can J Physiol Pharmacol 2012; 90:1029-59. [DOI: 10.1139/y2012-053] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.
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Affiliation(s)
- Josette M. Northcott
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Institute of Cardiovascular Sciences, and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Azadeh Yeganeh
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Carla G. Taylor
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Peter Zahradka
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Jeffrey T. Wigle
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Institute of Cardiovascular Sciences, and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
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27
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Lin C, Huang SJ, Wang N, Shen ZP. Relationship between plasma leptin levels and clinical outcomes of pediatric traumatic brain injury. Peptides 2012; 35:166-71. [PMID: 22764368 DOI: 10.1016/j.peptides.2012.03.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
High plasma leptin level has been associated with mortality after adult intracerebral hemorrhage. The present study was undertaken to investigate the plasma leptin concentrations in children with traumatic brain injury and to analyze the correlation of leptin with pediatric traumatic brain injury outcome. Plasma leptin concentration of eighty-nine healthy children and 142 children with acute severe traumatic brain injury was measured by enzyme-linked immunosorbent assay. Twenty-six patients (18.3%) died and 42 patients (29.6%) had an unfavorable outcome (Glasgow outcome scale score of 1-3) at 6 months after traumatic brain injury. Upon admission, plasma leptin level in patients was substantially higher than that in healthy controls. A forward stepwise logistic regression selected plasma leptin level as an independent predictor for 6-month mortality and unfavorable outcome of patients. A receiver operating characteristic curve analysis showed plasma leptin level better predicted 6-month mortality and unfavorable outcome. The prognostic value of leptin was similar to that of Glasgow Coma scale score for 6-month clinical outcomes. Thus, plasma leptin level represents a novel biomarker for predicting 6-month clinical outcome in children with traumatic brain injury.
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Affiliation(s)
- Chao Lin
- Department of Neurosurgery, The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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28
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Martin SS, Qasim AN, Rader DJ, Reilly MP. C-reactive protein modifies the association of plasma leptin with coronary calcium in asymptomatic overweight individuals. Obesity (Silver Spring) 2012; 20:856-61. [PMID: 21738237 PMCID: PMC4005808 DOI: 10.1038/oby.2011.164] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Evidence suggests putative interactions of leptin and C-reactive protein (CRP) in the pathogenesis of adiposity-related atherosclerotic cardiovascular disease (CVD). Therefore, we investigated whether CRP levels modify the relationship of leptin levels with coronary artery calcium (CAC). We examined 1,460 asymptomatic individuals from two community-based cross-sectional studies coordinated at a single, university-based research center. We focused on subjects who were overweight or obese (BMI ≥25) given greater biologic plausibility in this setting. In multivariable CAC models, we analyzed the interaction of log-transformed plasma leptin levels with higher CRP levels as defined by three cut-points: two clinically based (2 mg/l, 3 mg/l) and one dataset specific (sex-specific upper quartile). The association of plasma leptin with CAC was modified by higher CRP regardless of cut-point (interaction term P values all <0.01 in fully adjusted models). Leptin levels were associated with CAC in those with high, but not low CRP levels (e.g., tobit ratio for a 1 unit increase in ln(leptin) (95% CI): 2.18 (1.29-3.66) if CRP level ≥3 mg/l; N = 461 vs. 0.94 (0.67-1.31) if CRP levels <3 mg/l; N = 999) in fully adjusted models. No interaction with CRP was present in control analyses with adiponectin, BMI and waist circumference. In conclusion, in asymptomatic overweight and obese adults, increased leptin levels were independently associated with increased CAC in the presence of high, but not low CRP levels, supporting a leptin-CRP interface in atherosclerosis risk.
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Affiliation(s)
- Seth S. Martin
- Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Atif N. Qasim
- Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
| | - Dan J. Rader
- Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
- Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
| | - Muredach P. Reilly
- Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
- Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
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29
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Ong P, Sivanathan R, Borgulya G, Bizrah M, Iqbal Y, Andoh J, Gaze D, Kaski JC. Obesity, Inflammation and Brachial Artery Flow-Mediated Dilatation: Therapeutic Targets in Patients with Microvascular Angina (Cardiac Syndrome X). Cardiovasc Drugs Ther 2012; 26:239-44. [DOI: 10.1007/s10557-012-6382-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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30
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Bełtowski J. Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharmacol Physiol 2012; 39:168-178. [PMID: 21973116 DOI: 10.1111/j.1440-1681.2011.05623.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser(1177) , increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone.
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Affiliation(s)
- Jerzy Bełtowski
- Department of Pathophysiology, Medical University, Lublin, Poland.
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31
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Cirillo P, Maresca F, Di Palma V, Ziviello F, Bevilacqua M. Adipose tissue in the pathophysiology of cardiovascular disease: Who is guilty? World J Hypertens 2012; 2:13. [DOI: 10.5494/wjh.v2.i1.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Mechanism of the inhibitory effect of atorvastatin on leptin expression induced by angiotensin II in cultured human coronary artery smooth muscle cells. Clin Sci (Lond) 2011; 122:33-42. [DOI: 10.1042/cs20110114] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Leptin contributes to the pathogenesis of atherosclerosis. Ang II (angiotensin II), a proatherogenic cytokine, increases leptin synthesis in cultured adipocytes. Statin suppresses leptin expression in adipocytes and human coronary artery endothelial cells. However, the effect of Ang II and statin on leptin expression in VSMCs (vascular smooth muscle cells), the major cell types in atheroma, is poorly understood. Thus the aim of the present study was to investigate the molecular mechanism of atorvastatin for reducing leptin expression after Ang II stimulation in VSMCs. VSMCs from human coronary artery were cultured. Ang II stimulation increased leptin protein and mRNA and phospho-JNK (c-Jun N-terminal kinase) expression. Exogenous addition of Dp44mT (2,2′-dipyridyl-N,N-dimethylsemicarbazone) and mevalonate increased leptin protein expression similarly to Ang II. Atorvastatin, SP600125, JNK siRNA (small interfering RNA) and NAC (N-acetylcysteine) completely attenuated the leptin and phospho-JNK protein expression induced by Ang II. Ang II significantly increased ROS (reactive oxygen species) formation in human VSMCs. Addition of atorvastatin and NAC significantly attenuated the formation of ROS induced by Ang II. Addition of atorvastatin and SP600125 inhibited the phosphorylation of Rac1 induced by Ang II. The gel shift and promoter activity assay showed that Ang II increased AP-1 (activator protein-1)-binding activity and leptin promoter activity, while SP600125, NAC and atorvastatin inhibited the AP-1-binding activity and leptin promoter activity induced by Ang II. Ang II significantly increased the migration and proliferation of cultured VSMCs, while addition of atorvastatin, SP600125, NAC and leptin siRNA before Ang II stimulation significantly inhibited the migration and proliferation of VSMCs induced by Ang II. Ang II significantly increased secretion of leptin from human VSMCs, and addition of SP600125, atorvastatin and NAC before Ang II stimulation almost completely inhibited the leptin secretion induced by Ang II. In conclusion, Ang II induces leptin expression in human VSMCs, and atorvastatin could inhibit the leptin expression induced by Ang II. The inhibitory effect of atorvastatin on Ang II-induced leptin expression was mediated by Rac, ROS and JNK pathways.
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Mugabo Y, Mukaneza Y, Renier G. Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction. Metabolism 2011; 60:640-8. [PMID: 20727556 DOI: 10.1016/j.metabol.2010.06.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Revised: 05/22/2010] [Accepted: 06/21/2010] [Indexed: 12/21/2022]
Abstract
Circulating levels of free fatty acids are commonly elevated in patients with the metabolic syndrome and exert, through activating proinflammatory pathways, harmful effects of the vascular endothelium. In this study, we examined the effect of palmitate (PA) on endothelial C-reactive protein (CRP) expression and the role of CRP in PA-induced nitric oxide (NO) inhibition. Palmitate increased, in a dose-dependent manner, CRP protein expression and production in human aortic endothelial cells (HAECs). Induction of CRP protein was mimicked by ceramide, whereas bromopalmitate and other common free fatty acids such as oleate or linoleate were ineffective. Palmitate also elicited reactive oxygen species production in HAECs, an effect prevented by protein kinase C (PKC) inhibition and adenosine monophosphate-activated kinase (AMPK) activation. Palmitate-treated HAECs showed increased CRP messenger RNA expression and nuclear factor (NF)-κB activation. Induction of CRP expression by PA was prevented by antioxidants and normalized by PKC and mitogen-activated protein kinase inhibitors. Disrupting NF-κB and Janus kinase/signal transducers and activators of transcription pathways or inducing AMPK activation also suppressed the stimulatory effect of PA on CRP messenger RNA expression. Finally, in HAECs, PA reduced NO release, an effect reversed by anti-CRP antibody. These data demonstrate that PA-induced endothelial CRP expression involves PKC-driven oxidative stress, possibly through AMPK inhibition, and activation of downstream redox-sensitive signaling pathways, including NF-κB. They further support a role for endothelial cell-derived CRP as mediator of the suppressive effect of PA on NO production.
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Affiliation(s)
- Yves Mugabo
- Centre Hospitalier de l'Université de Montréal Research Centre, Notre-Dame Hospital, Department of Medicine, Montreal, Quebec, Canada
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Liang J, Feng J, Wu WKK, Xiao J, Wu Z, Han D, Zhu Y, Qiu G. Leptin-mediated cytoskeletal remodeling in chondrocytes occurs via the RhoA/ROCK pathway. J Orthop Res 2011; 29:369-74. [PMID: 20886658 DOI: 10.1002/jor.21257] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 08/16/2010] [Indexed: 02/04/2023]
Abstract
Leptin affects a number of cell signaling pathways, at present, the mechanism(s) by which leptin affects the cartilage cells in OA patient is not well understood. The current study seeks to elucidate whether leptin induces cytoskeletal remodeling in chondrocytes and the possible involvement of the RhoA/ROCK pathway and its downstream mediators in this process. Fluorescent resonance energy transfer (FRET) and western analysis were used to determine the activations of the key proteins in the RhoA/LIMK1/Cofilin pathway. Accompanying cytoskeletal remodeling was elucidated. Upon leptin stimulation, a substantial increase of RhoA activity localized at one end of the cell was observed from 2 to 30 min post-stimulation. The results of Western blot showed leptin significantly increased LIMK1 and cofilin-2 phosphorylation in a time-dependent manner with maximal stimulation attained 60 min and 24 h post-stimulation, respectively. Chondrocytes stimulated with leptin exhibited an epithelioid morphology with increased cellular spreading. F-actin in leptin-stimulated chondrocytes also showed more intense cytoplasmic staining with occasional localization along filamentous structures. The results indicate that leptin activates the RhoA/ROCK/LIMK/cofilin pathway, which results in cytoskeletal reorganization in chondrocytes. These findings provide novel evidence supporting the possible involvement of leptin and the RhoA pathway in the pathogenesis of OA.
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Affiliation(s)
- Jinqian Liang
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
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35
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Relevance of disease- and organ-specific endothelial cells forin vitroresearch. Cell Biol Int 2010; 34:1231-8. [DOI: 10.1042/cbi20100531] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice. J Hypertens 2010; 28:2111-9. [DOI: 10.1097/hjh.0b013e32833ca68c] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, Tune JD. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol 2010; 30:1711-7. [PMID: 20576943 PMCID: PMC2924445 DOI: 10.1161/atvbaha.110.210070] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of endothelial NO synthase by protein kinase C (PKC)-beta. However, our understanding of how PVAT potentially contributes to coronary disease as a complication of obesity/metabolic syndrome (MetS) remains limited. The current study investigated whether PVAT-derived leptin impairs coronary vascular function via PKC-beta in MetS. METHODS AND RESULTS Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw miniature swine for isometric tension studies. Endothelial-dependent vasodilation to bradykinin was significantly reduced in MetS. PVAT did not affect bradykinin-mediated dilation in arteries from lean swine but significantly exacerbated endothelial dysfunction in arteries from MetS swine. PVAT-induced impairment was reversed by inhibition of either PKC-beta with ruboxistaurin (Eli Lilly and Company, Indianapolis, Ind) or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western blot and immunohistochemical analyses demonstrated increased PVAT-derived leptin and coronary leptin receptor density with MetS. Coronary PKC-beta activity was increased in both MetS arteries exposed to PVAT and lean arteries exposed to leptin. Finally, leptin-induced endothelial dysfunction was reversed by ruboxistaurin. CONCLUSIONS Increases in epicardial PVAT leptin exacerbate coronary endothelial dysfunction in MetS via a PKC-beta-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.
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Affiliation(s)
- Gregory A Payne
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Time Course of Plasma Leptin Concentrations After Acute Spontaneous Basal Ganglia Hemorrhage. World Neurosurg 2010; 74:286-93. [DOI: 10.1016/j.wneu.2010.02.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 02/05/2010] [Indexed: 11/19/2022]
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Abstract
OBJECTIVE Leptin is associated with blood pressure (BP) in experimental and cross-sectional studies, but only one previous prospective study of middle-aged men has reported the association between leptin and incident hypertension. We examined the association of leptin levels with incident hypertension in a population-based study of older men and women. DESIGN Longitudinal cohort study. POPULATION Participants were 602 community-dwelling older adults with normal baseline BP levels who attended a research clinic visit between 1984 and 1987 and again 4.4 years later (mean age was 66.2 +/- 11.4; 60.6% were men; mean body mass index (BMI) 24.9 +/- 3.4 kg/m(2)). MEASUREMENTS Hypertension was defined as systolic BP > or =140 mmHg and/or diastolic BP > or =90 mmHg and/or antihypertensive drug treatment. Leptin was measured by radioimmunoassay. RESULTS After an average 4.4-year follow-up (minimum 2-maximum 7 years), 106 (17.6%) new cases of hypertension were identified. At baseline, participants who developed hypertension were older and had higher systolic BP and higher total cholesterol compared to participants who remained normotensive. Baseline serum leptin levels were higher in participants who developed hypertension compared to persistent normotensives [median (25th-75th range)] [8.8(5-16) vs 7(4-11) ng/ml, P = 0.002]. In logistic regression models, leptin (log-transformed) predicted incident hypertension before and after adjustments for baseline age, BMI, systolic BP, total cholesterol, medications, and previous cardiovascular disease (OR 1.75 95% CI 1.17-2.61, P = 0.006). This association persisted after exclusion of 45 obese participants. CONCLUSION Higher leptin levels were independently associated with increased odds of incident hypertension in older adults.
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Affiliation(s)
- Caroline K. Kramer
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
- Endocrine Division, Hospital de Clínicas de Porto Alegre/Programa de Pós -graduação em Ciencias Médicas: Endocrinologia, Porto Alegre/RS, Brazil
| | - Denise von Mühlen
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
| | - Elizabeth Barrett-Connor
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
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Sun YM, Li J, Luan Y, Wang LF. Effect of statin therapy on leptin levels in patients with coronary heart disease. Peptides 2010; 31:1205-7. [PMID: 20338208 DOI: 10.1016/j.peptides.2010.03.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2010] [Revised: 03/17/2010] [Accepted: 03/17/2010] [Indexed: 01/08/2023]
Abstract
The goal of this study was to investigate the effects of simvastatin on the levels of plasma leptin and nitric oxide (NO) in patients with coronary heart disease (CHD). The study population consisted of 65 patients with CHD and 48 control individuals without signs or symptoms of CHD. The patients with CHD were treated with simvastatin 20mg/day. Fasting serum lipids, leptin and NO were determined before and after 12 weeks of treatment. Leptin levels were higher in patients with CHD than control (P<0.05). Statin treatment significantly decreased plasma lipids and leptin levels and increased NO concentration in all CHD patients (P<0.05). Serum leptin levels after treatment correlated negatively with the NO concentration (P<0.05). Simvastatin may provide beneficial effects of reducing leptin levels, independent of its lipid-lowering action, which may play an important role in patients with CHD.
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Affiliation(s)
- Yan-Ming Sun
- Department of Cardiac Care Unit, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin 150001, China
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Bełtowski J, Wójcicka G, Jamroz-Wiśniewska A, Wojtak A. Chronic hyperleptinemia induces resistance to acute natriuretic and NO-mimetic effects of leptin. Peptides 2010; 31:155-63. [PMID: 19854228 DOI: 10.1016/j.peptides.2009.10.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 10/14/2009] [Accepted: 10/14/2009] [Indexed: 12/21/2022]
Abstract
Apart from controlling energy balance, leptin, secreted by adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have demonstrated that acutely administered leptin stimulates natriuresis and vascular nitric oxide (NO) production and that these effects are impaired in obese animals. However, the mechanism of resistance to leptin is not clear. Because obesity is associated with chronically elevated leptin, we examined if long-term hyperleptinemia impairs acute effects of leptin on sodium excretion and NO production in the absence of obesity. Hyperleptinemia was induced in lean rats by administration of exogenous leptin at a dose of 0.5mg/kg/day for 7 days, and then acute effect of leptin (1mg/kg i.v.) was studied under general anesthesia. Leptin increased fractional sodium excretion and decreased Na(+),K(+)-ATPase activity in the renal medulla. In addition, leptin increased the level of NO metabolites and cyclic GMP in plasma and aortic wall. These acute effects of leptin were impaired in hyperleptinemic animals. In both control and hyperleptinemic groups the effect of leptin on Na(+) excretion and renal Na(+),K(+)-ATPase was abolished by phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not by protein kinase B/Akt inhibitor, triciribine,. In contrast, acute effect of leptin on NO metabolites and cGMP was abolished by triciribine but not by wortmannin. Leptin stimulated Akt phosphorylation at Ser(473) in aortic tissue but not in the kidney, and this effect was comparable in control and hyperleptinemic groups. These results suggest that hyperleptinemia may mediate "renal" and "vascular" leptin resistance observed in obesity.
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Affiliation(s)
- Jerzy Bełtowski
- Department of Pathophysiology, Medical University, Lublin, Poland.
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