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Grossini E, Venkatesan S, Ola Pour MM, Ferrante D, Surico D, Vaschetto R, Cantaluppi V, Pirisi M. Chromogranin B Protects Human Umbilical Endothelial Cells against Oxidative Stress. Int J Mol Sci 2024; 25:10296. [PMID: 39408626 PMCID: PMC11476595 DOI: 10.3390/ijms251910296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024] Open
Abstract
Chromogranin B (CgB) is involved in the control of the cardiovascular system through the regulation of catecholamine release. Whether CgB can exert direct actions on the endothelium has not yet been clarified. Here, we aimed to investigate the effects of CgB on cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), glutathione (GSH), nitric oxide (NO) release, and the cytosolic calcium concentration ([Ca2+]c) in human vascular endothelial cells (HUVECs) cultured under both physiological and peroxidative conditions. In HUVECs, experiments were conducted to establish the proper concentration and timing of CgB stimulation. Thereafter, specific assays were used to evaluate the response of HUVECs cultured in physiologic or oxidative stress conditions to CgB in the presence or absence of β-adrenergic receptor agonists and antagonists and intracellular pathways blockers. Analysis of cell viability, mitochondrial membrane potential, and NO release revealed that CgB was able to cause increased effects in HUVECs cultured in physiological conditions. Additionally, the same analyses performed in HUVECs cultured with H2O2, showed protective effects exerted by CgB, which was also able to counteract ROS release and maintain GSH levels. Furthermore, CgB played a dual role on the [Ca2+]c depending on the physiological or peroxidative cell culturing conditions. In conclusion, our data provide new information about the direct role of CgB in the physiological regulation of endothelial function and highlight its potential as a protective agent against peroxidative conditions, such as those found in cardiovascular diseases.
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Affiliation(s)
- Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Sakthipriyan Venkatesan
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Mohammad Mostafa Ola Pour
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Daniela Ferrante
- Statistical Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Daniela Surico
- Gynecology and Obstetrics, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Rosanna Vaschetto
- Anesthesia and Intensive Care, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Vincenzo Cantaluppi
- Nephrology Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Mario Pirisi
- Internal Medicine Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
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Zdanowicz A, Urban S, Ponikowska B, Iwanek G, Zymliński R, Ponikowski P, Biegus J. Novel Biomarkers of Renal Dysfunction and Congestion in Heart Failure. J Pers Med 2022; 12:jpm12060898. [PMID: 35743683 PMCID: PMC9224642 DOI: 10.3390/jpm12060898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/15/2022] [Accepted: 05/26/2022] [Indexed: 02/04/2023] Open
Abstract
Heart failure is a major public health problem and, despite the constantly emerging, new, effective treatments, it remains a leading cause of morbidity and mortality. Reliable tools for early diagnosis and risk stratification are crucial in the management of HF. This explains a growing interest in the development of new biomarkers related to various pathophysiological mechanisms of HF. In the course of this review, we focused on the markers of congestion and renal dysfunction in terms of their interference with cardiovascular homeostasis. Congestion is a hallmark feature of heart failure, contributing to symptoms, morbidity, and hospitalizations of patients with HF and has, therefore, become a therapeutic target in AHF. On the other hand, impaired renal function by altering the volume status contributes to the development and progression of HF and serves as a marker of an adverse clinical outcome. Early detection of congestion and an adequate assessment of renal status are essential for the prompt administration of patient-tailored therapy. This review provides an insight into recent advances in the field of HF biomarkers that could be potentially implemented in diagnosis and risk stratification of patients with HF.
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Affiliation(s)
- Agata Zdanowicz
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Szymon Urban
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
- Correspondence: ; Tel.: +48-71-733-11-12
| | - Barbara Ponikowska
- Student Scientific Organization, Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland;
| | - Gracjan Iwanek
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Robert Zymliński
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Piotr Ponikowski
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Jan Biegus
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
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3
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Performance Evaluation of the KRYPTOR Compact PLUS Analyzer-Based B.R.A.H.M.S. CgA Ⅱ KRYPTOR Assay for Chromogranin A Measurement. Diagnostics (Basel) 2021; 11:diagnostics11122400. [PMID: 34943638 PMCID: PMC8700334 DOI: 10.3390/diagnostics11122400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 12/04/2022] Open
Abstract
Numerous immunoassays have been developed to measure the levels of chromogranin A (CgA), a useful biomarker for diagnosing and monitoring generally heterogeneous neuroendocrine tumors (NETs). Here, we evaluated the imprecision and linearity of three such assays: KRYPTOR (ThermoFisher Scientific), NEOLISA (EuroDiagnostica), and CgA-RIA (CisBio), using 123 samples for each assay. The correlation coefficients between the assays were 0.932 (CgA-RIA versus NEOLISA), 0.956 (KRYPTOR versus CgA-RIA), and 0.873 (NEOLISA versus KRYPTOR). KRYPTOR showed good precision, with percent coefficients of variation less than 5% for low and high concentration quality controls. Linearity was maintained over a wide concentration range. Comparison of CgA levels from three disease entities (NETs, non-NET pancreatic tumors, and prostate cancer) and healthy controls showed that patients with NETs had significantly higher CgA levels (n = 57, mean: 1.82 ± 0.43 log ng/mL) than healthy individuals (n = 20, mean: 1.51 ± 0.23 log ng/mL; p = 0.018). No other significant differences between groups were observed. All three immunoassays showed strong correlations in measured CgA levels. Because KRYPTOR operation uses a fully automated random-access system and requires shorter incubation times and smaller sample volumes, the KRYPTOR assay may improve laboratory workflow while maintaining satisfactory analytical performance.
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The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease. Int J Mol Sci 2021; 22:ijms22116118. [PMID: 34204153 PMCID: PMC8201018 DOI: 10.3390/ijms22116118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.
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Tüten N, Güralp O, Gök K, Hamzaoglu K, Oner YO, Makul M, Bulut H, Irmak K, Tüten A, Malik E. Serum catestatin level is increased in women with preeclampsia. J OBSTET GYNAECOL 2021; 42:55-60. [PMID: 33938370 DOI: 10.1080/01443615.2021.1873922] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Catestatin can inhibit catecholamine release from chromaffin cells and adrenergic neurons. Catestatin can also have a strong vasodilator effect. This may be useful in understanding the pathophysiology of preeclampsia and its treatment. In this study, we investigated the serum catestatin levels in pregnant women with and without preeclampsia. Fifty consecutive women with mild preeclampsia, 50 consecutive women with severe preeclampsia, and 100 consecutive pregnant women with a gestational age-matched (±1 week) uncomplicated pregnancy were evaluated in a cross-sectional study. Mean serum catestatin was significantly increased in the preeclampsia group compared to the control group (290.7 ± 95.5 pg/mL vs. 182.8 ± 72.0 pg/mL). Mean serum catestatin was comparable in mild and severe preeclampsia groups (282.7 ± 97.9 pg/mL vs. 298.7 ± 93.4 pg/mL, p = .431). Serum catestatin levels had positive correlations with systolic and diastolic blood pressure, urea, uric acid, and creatinine. In conclusion, serum catestatin levels are increased in preeclamptic pregnancies compared to gestational age-matched controls.IMPACT STATEMENTWhat is already known on this subject? The role of autonomic nervous system dysregulation in the pathophysiology of preeclampsia is known. The most obvious part of this dysregulation is the sympathetic nervous system activation. The adrenal medulla is one of the locations of the sympathetic nervous system in the body.What do the results of this study add? Serum catestatin levels were found to be correlated with clinical and laboratory data of preeclampsia. This highlights the importance of chromaffin cell secretions in the adrenal medulla in preeclampsia.What are the implications of these findings for clinical practice and/or further research? This study will help understand the role of the adrenal medulla in the autonomic nervous system dysregulation in preeclampsia. Also, control of serum catestatin levels may support the treatment of hypertension in preeclampsia.
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Affiliation(s)
- Nevin Tüten
- Obstetrics and Gynecology Istanbul, Kanuni Sultan Suleyman Education and Research Hospital, Turkey
| | - Onur Güralp
- Carl von Ossietzky Oldenburg University, University Hospital for Gynecology and Obstetrics, Klinikum Oldenburg AöR, Oldenburg, Germany
| | - Koray Gök
- Education and Research Hospital, Obstetrics and Gynecology, Sakarya University, Sakarya, Turkey
| | - Kübra Hamzaoglu
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Yahya Ozgün Oner
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Melike Makul
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Huri Bulut
- Faculty of Medicine, Medical Biochemistry Department, Istinye University, Istanbul, Turkey
| | - Kübra Irmak
- Department of Obstetrics and Gynaecology, Tokat State Hospital, Tokat, Turkey
| | - Abdullah Tüten
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Eduard Malik
- Carl von Ossietzky Oldenburg University, University Hospital for Gynecology and Obstetrics, Klinikum Oldenburg AöR, Oldenburg, Germany
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Yibirin M, De Oliveira D, Valera R, Plitt AE, Lutgen S. Adverse Effects Associated with Proton Pump Inhibitor Use. Cureus 2021; 13:e12759. [PMID: 33614352 PMCID: PMC7887997 DOI: 10.7759/cureus.12759] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 12/13/2022] Open
Abstract
Proton pump inhibitors (PPIs) marked a before and after in the management of gastric acid-related disorders since their introduction to the market in 1989. Due to a novel, highly effective mechanism of action blocking the last converging step of gastric acid secretion by parietal cells and very few and mostly tolerable side effects, these drugs quickly displaced other pharmacological compounds such as H2 antagonists as the first treatment choice for peptic ulcer disease, gastroesophageal ulcers, Zollinger-Ellison syndrome, nonsteroidal anti-inflammatory drug-associated ulcers, and eradication of Helicobacter pylori, leading to an exponential increase in their prescription up to now. However, widespread PPI use has led to emerging evidence of long-term adverse effects not described previously, including increased risk of kidney, liver, and cardiovascular disease, dementia, enteroendocrine tumors of the gastrointestinal tract, susceptibility to respiratory and gastrointestinal infections, and impaired absorption of nutrients. Although the evidence published thus far has not established strong correlations, it has been relevant enough to raise new questions about PPIs' safety profile and reconsideration of their clinical indications. Hence, the aim of this review is to evaluate the association between PPI use and the risk of serious adverse effects given increasing concerns about the overuse of PPIs in the general population.
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Affiliation(s)
- Marcel Yibirin
- Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Diana De Oliveira
- Department of Research, Foundation for Clinic, Public Health, and Epidemiological Research of Venezuela (FISPEVEN), Caracas, VEN
| | - Roberto Valera
- Department of General Surgery, Cleveland Clinic Florida, Weston, USA
| | - Andrea E Plitt
- Critical Care, Dr. Ignacio Pirovano Hospital, Buenos Aires, ARG
| | - Sophia Lutgen
- Internal Medicine, Dr Juan A. Fernández Hospital, Buenos Aires, ARG
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Manolis AA, Manolis TA, Melita H, Katsiki N, Manolis AS. Proton pump inhibitors and cardiovascular adverse effects: Real or surreal worries? Eur J Intern Med 2020; 72:15-26. [PMID: 31796246 DOI: 10.1016/j.ejim.2019.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/21/2019] [Accepted: 11/24/2019] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors (PPIs) are among the most widely prescribed agents, either for treatment or prophylaxis of gastrointestinal (GI) disease, that are often administered for prolonged or chronic use. Patients with cardiovascular (CV) disease frequently receive PPIs for prophylaxis against GI bleeding due to common use of antithrombotic drugs. Over the last several years there is a growing number of reports associating chronic PPI use with a variety of serious CV and non-CV adverse effects. In this context, PPI use has been independently associated with an increased risk of CV morbidity (myocardial infarction, stroke, other CV events) and mortality. However, the critique remains that these data do not largely derive from randomized controlled trials. On the other hand, in certain conditions, the benefits of PPIs may outweigh the risks of adverse CV effects. As the indications for prolonged, particularly lifelong, prophylactic use of PPIs are not compelling and in the light of evidence of serious CV and other adverse effects, clinicians have to reconsider such long-term use of these drugs. Importantly, histamine 2 blockers have not been found to be associated with increased CV risk and thus may be an alternative therapeutic option in certain patients. These issues are amply discussed together with the potential mechanisms of these pleiotropic and off-target effects of PPIs, which are also depicted in an illustrative schema; data are also presented on differential effects of specific agents involved, alternative modes of therapy available, and relevant current guidelines on this issue.
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Affiliation(s)
| | | | | | - Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece
| | - Antonis S Manolis
- Third and First Department of Cardiology, Athens University School of Medicine, Ippokrateio Hospital, Vas. Sofias 114, Athens 115 27, Greece.
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8
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Alam MJ, Gupta R, Mahapatra NR, Goswami SK. Catestatin reverses the hypertrophic effects of norepinephrine in H9c2 cardiac myoblasts by modulating the adrenergic signaling. Mol Cell Biochem 2019; 464:205-219. [PMID: 31792650 DOI: 10.1007/s11010-019-03661-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypothesized that CST moderates the adrenergic overdrive and studied its effects on norepinephrine-mediated hypertrophic responses in H9c2 cardiac myoblasts. CST alone regulated the expression of a number of fetal genes that are induced during hypertrophy. When cells were pre-treated CST, it blunted the modulation of those genes by norepinephrine. Norepinephrine (2 µM) treatment also increased cell size and enhanced the level of Troponin T in the sarcomere. These effects were attenuated by the treatment with CST. CST attenuated the immediate generation of ROS and the increase in glutathione peroxidase activity induced by norepinephrine treatment. Expression of fosB and AP-1 promoter-reporter constructs was used as the endpoint readout for the interaction between the CST and adrenergic signals at the gene level. It showed that CST largely attenuates the stimulatory effects of norepinephrine and other mitogenic signals through the modulation of the gene regulatory modules in a characteristic manner. Depending upon the dose, the signaling by CST appears to be disparate, and at 10-25 nM doses, it primarily moderated the signaling by the β1/2-adrenoceptors. This study, for the first time, provides insights into the modulation of adrenergic signaling in the heart by CST.
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Affiliation(s)
- Md Jahangir Alam
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Fridabad, 121001, India
| | - Richa Gupta
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Shyamal K Goswami
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Fridabad, 121001, India.
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9
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Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann N Y Acad Sci 2019; 1455:34-58. [PMID: 31588572 PMCID: PMC6899468 DOI: 10.1111/nyas.14249] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/09/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
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Affiliation(s)
- Sushil K Mahata
- VA San Diego Healthcare System, San Diego, California.,Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Angelo Corti
- IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
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10
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Rocca C, Scavello F, Colombo B, Gasparri AM, Dallatomasina A, Granieri MC, Amelio D, Pasqua T, Cerra MC, Tota B, Corti A, Angelone T. Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity. FASEB J 2019; 33:7734-7747. [PMID: 30973759 DOI: 10.1096/fj.201802707r] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose-dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full-length recombinant CgA on Doxo-induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo-induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury. On the other hand, CgA did not impair the anticancer activity of Doxo in all the murine models investigated. Furthermore, we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low-dose CgA to patients with low levels of endogenous CgA might represent a novel approach to prevent Doxo-induced adverse events without impairing antitumor effects.-Rocca, C., Scavello, F., Colombo, B., Gasparri, A. M., Dallatomasina, A., Granieri, M. C., Amelio, D., Pasqua, T., Cerra, M. C., Tota, B., Corti, A., Angelone, T. Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Francesco Scavello
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Barbara Colombo
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Anna Maria Gasparri
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Alice Dallatomasina
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Maria Concetta Granieri
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Daniela Amelio
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Maria Carmela Cerra
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Bruno Tota
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Angelo Corti
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
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11
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Guest PC. Biogenesis of the Insulin Secretory Granule in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:17-32. [PMID: 30919330 DOI: 10.1007/978-3-030-12668-1_2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The secretory granules of pancreatic beta cells are specialized organelles responsible for the packaging, storage and secretion of the vital hormone insulin. The insulin secretory granules also contain more than 100 other proteins including the proteases involved in proinsulin-to insulin conversion, other precursor proteins, minor co-secreted peptides, membrane proteins involved in cell trafficking and ion translocation proteins essential for regulation of the intragranular environment. The synthesis, transport and packaging of these proteins into nascent granules must be carried out in a co-ordinated manner to ensure correct functioning of the granule. The process is regulated by many circulating nutrients such as glucose and can change under different physiological states. This chapter discusses the various processes involved in insulin granule biogenesis with a focus on the granule composition in health and disease.
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Affiliation(s)
- Paul C Guest
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
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12
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Corti A, Marcucci F, Bachetti T. Circulating chromogranin A and its fragments as diagnostic and prognostic disease markers. Pflugers Arch 2017; 470:199-210. [PMID: 29018988 DOI: 10.1007/s00424-017-2030-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 12/19/2022]
Abstract
Chromogranin A (CgA), a secretory protein released in the blood by neuroendocrine cells and neurons, is the precursor of various bioactive fragments involved in the regulation of the cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair. After the original demonstration that circulating CgA can serve as a biomarker for a wide range of neuroendocrine tumors, several studies have shown that increased levels of CgA can be present also in the blood of patients with cardiovascular, gastrointestinal, and inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. Considering the high structural and functional heterogeneity of the CgA system, comprising precursor and fragments, it is not surprising that the different immunoassays used in these studies led, in some cases, to discrepant results. Here, we review these notions and we discuss the importance of measuring total-CgA, full-length CgA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system.
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Affiliation(s)
- Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. .,Vita-Salute San Raffaele University, Milan, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Tiziana Bachetti
- Clinical Trials Centre, Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Pavia, Italy
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Rogowski W, Wachuła E, Lewczuk A, Kolasińska-Ćwikła A, Iżycka-Świeszewska E, Sulżyc-Bielicka V, Ćwikła JB. Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors. Future Oncol 2017; 13:1069-1079. [DOI: 10.2217/fon-2016-0455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. Patients & methods: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. Results: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. Conclusion: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.
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Affiliation(s)
- Wojciech Rogowski
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
| | - Ewa Wachuła
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Lewczuk
- Department of Endocrinology, Medical University of Gdańsk, Gdańsk, Poland
| | - Agnieszka Kolasińska-Ćwikła
- Department of Clinical Oncology, Maria-Skłodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
| | | | | | - Jarosław B Ćwikła
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
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14
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Gkolfinopoulos S, Tsapakidis K, Papadimitriou K, Papamichael D, Kountourakis P. Chromogranin A as a valid marker in oncology: Clinical application or false hopes? World J Methodol 2017; 7:9-15. [PMID: 28396845 PMCID: PMC5366937 DOI: 10.5662/wjm.v7.i1.9] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 12/15/2016] [Accepted: 01/03/2017] [Indexed: 02/06/2023] Open
Abstract
Chromogranin A, due to its primary expression throughout the neuroendocrine system, is a widely accepted biomarker for the assessment of neuro-endocrine tumors. It has been traditionally used in the management of patients with tumors of gastro-enteropancreatic origin. Lately, it has also been implicated in various conditions and diseases, both benign and malignant. However, the paucity of data of adequate strength, as well as its relation with common physiologic conditions and its interaction with commonly prescribed medications, limit its clinical use in only a narrow spectrum. Herein, we present a thorough review to the most frequent conditions where its levels are affected, focusing specifically on its potential use as a prognostic and predictive biomarker in oncology.
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15
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Cheng YY, An JD, Feng S, Ge W. [Changes in serum chromogranin A and urotensin II levels in children with chronic heart failure]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2017; 19:313-317. [PMID: 28302203 PMCID: PMC7390140 DOI: 10.7499/j.issn.1008-8830.2017.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 12/21/2016] [Indexed: 06/06/2023]
Abstract
OBJECTIVE To examine the changes in serum chromogranin A (CgA) and urotensin II (U II) levels in children with chronic heart failure (CHF) and their clinical significance. METHODS A total of 58 children with CHF, among whom 17 had endocardial fibroelastosis (EFE) and 41 had dilated cardiomyopathy (DCM), were selected as CHF group, and 20 healthy children were selected as control group. Serum levels of CgA and U II were measured using enzyme-linked immunosorbent assay, and the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) was determined by bi-directional lateral flow immunoassay. Ventricular remodeling indices were measured using echocardiography. The correlation between serum CgA and U II levels and ventricular remodeling was evaluated by Pearson correlation or Spearman's rank correlation analysis. RESULTS There were no significant differences in serum CgA and NT-proBNP levels between children with grade II heart function and the control group (P>0.05). However, the serum CgA and NT-proBNP levels gradually increased as the heart function grade increased, and were significantly higher in grade III and IV children compared to those in the control group (P<0.05). U II levels were lower in children with grade II, III, or IV heart function than those in the control group (P<0.05), and significantly decreased with the aggravation of CHF (P<0.05). There were no significant differences in CgA and U II levels between patients with EFE and DCM (P>0.05). Serum CgA concentration was positively correlated with left ventricular mass index (LVMI), NT-proBNP, and cardiac function classification (r=0.279, 0.649, and 0.778 respectively; P<0.05), but was negatively correlated with left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and U II (r=-0.369, -0.322, and -0.718 respectively; P<0.05). Serum U II concentration was negatively correlated with NT-proBNP and cardiac function classification (r=-0.472 and -0.591 respectively; P<0.05), but was not correlated with LVMI, LVEF, and LVFS (P>0.05). CONCLUSIONS CgA may play a role in ventricular remodeling in children with CHF. Serum CgA and U II may serve as a reference for the diagnosis and functional classification of heart failure.
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Affiliation(s)
- Yao-Yao Cheng
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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16
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Srithunyarat T, Hagman R, Höglund OV, Olsson U, Stridsberg M, Jitpean S, Lagerstedt AS, Pettersson A. Catestatin and vasostatin concentrations in healthy dogs. Acta Vet Scand 2017; 59:1. [PMID: 28049540 PMCID: PMC5210291 DOI: 10.1186/s13028-016-0274-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 12/23/2016] [Indexed: 12/31/2022] Open
Abstract
Background The neuroendocrine glycoprotein chromogranin A is a useful biomarker in humans for neuroendocrine tumors and stress. Chromogranin A can be measured in both blood and saliva. The objective of this study was to investigate concentrations of and correlation between the chromogranin A epitopes catestatin and vasostatin in healthy dogs accustomed to the sample collection procedures. Blood and saliva samples were collected from 10 research Beagle dogs twice daily for 5 consecutive days, and from 33 privately-owned blood donor dogs in association with 50 different blood donation occasions. All dogs were familiar with sample collection procedures. During each sampling, stress behavior was scored by the same observer using a visual analog scale (VAS) and serum cortisol concentrations. Catestatin and vasostatin were analyzed using radioimmunoassays for dogs. Results The dogs showed minimal stress behavior during both saliva sampling and blood sampling as monitored by VAS scores and serum cortisol concentrations. Few and insufficient saliva volumes were obtained and therefore only catestatin could be analyzed. Catestatin concentrations differed significantly and did not correlate significantly with vasostatin concentrations (P < 0.0001). Age, gender, breed, and time of sample collection did not significantly affect concentrations of plasma catestatin, vasostatin, and saliva catestatin. Conclusions The normal ranges of plasma catestatin (0.53–0.98 nmol/l), vasostatin (0.11–1.30 nmol/l), and saliva catestatin (0.31–1.03 nmol/l) concentrations in healthy dogs accustomed to the sampling procedures were determined. Separate interpretation of the different chromogranin A epitopes from either saliva or plasma is recommended.
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Xu W, Yu H, Wu H, Li S, Chen B, Gao W. Plasma Catestatin in Patients with Acute Coronary Syndrome. Cardiology 2016; 136:164-169. [PMID: 27681934 DOI: 10.1159/000448987] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/09/2016] [Indexed: 11/19/2022]
Abstract
OBJECTIVES To measure plasma catestatin levels in patients with acute coronary syndrome and investigate whether there is an association between catestatin levels and long-term outcome. METHODS Patients (n = 170) with suspected acute coronary syndrome who underwent emergency coronary angiography were enrolled, including 46 with acute ST-segment elevation myocardial infarction (STEMI), 89 with unstable angina pectoris (UAP), and 35 without coronary artery disease (CAD). All patients were followed for 2 years to measure the occurrence of major adverse cardiovascular events (MACEs), including death from a cardiovascular cause, recurrent acute myocardial infarction, or hospital admission for heart failure or revascularization. RESULTS On average, the plasma catestatin levels in patients with STEMI (0.80 ± 0.62 ng/ml) and UAP (0.99 ± 0.63 ng/ml) were significantly lower than the levels seen in the control group with no evidence of CAD (1.38 ± 0.98 ng/ml; p = 0.001). In multivariable linear regression, body mass index, presence of hypertension, and type of CAD were independently related to the plasma catestatin level. However, there were no significant differences in MACEs between patients with high and low levels of catestatin. CONCLUSIONS The plasma catestatin levels in patients with STEMI and UAP were lower than the levels seen in patients without CAD.
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Affiliation(s)
- Weixian Xu
- Department of Cardiology, Peking University Third Hospital, Beijing, China
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18
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Abstract
Chromogranin A (CgA) is an established plasma marker of neuroendocrine tumors and has been suggested to also have a role as biomarker in other diseases. Whether CgA has any role as biomarker in diabetes is, however, unresolved, but its widespread distribution in the secretory granules in endocrine tissues including β cells and α cells in pancreas, and the metabolic effects of its peptide fragments suggest that CgA may play a pathophysiological role in diabetes, and thus also be a potential diabetes biomarker. In this review, we summarize the available information on CgA and some of its functional post-translational cleavage products in diabetes, followed by a discussion of its potential as a plasma marker in diabetes and the methodological concerns involved.
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Affiliation(s)
- Kasper Broedbaek
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Linda Hilsted
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
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Xu W, Yu H, Li W, Gao W, Guo L, Wang G. Plasma Catestatin: A Useful Biomarker for Coronary Collateral Development with Chronic Myocardial Ischemia. PLoS One 2016; 11:e0149062. [PMID: 27304618 PMCID: PMC4909297 DOI: 10.1371/journal.pone.0149062] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 01/27/2016] [Indexed: 11/18/2022] Open
Abstract
Backgrounds Catestatin is an endogenous multifunctional neuroendocrinepeptide. Recently, catestatin was discovered as a novel angiogenic cytokine. The study was to investigate the associations between endogenous catestatin and coronary collateral development among the patients with chronic myocardial ischemia. Methods Thirty-eight patients with coronary artery chronic total occlusions (CTO) (CTO group) and 38 patients with normal coronary arteries (normal group) were enrolled in the series. Among the patients with CTO, coronary collateral development was graded according to the Rentrop score method. Rentrop score 0–1 collateral development was regarded as poor collateral group and 2–3 collateral development was regarded as good collateral group. Plasma catestatin level and vascular endothelial growth factor (VEGF) were measured by ELISA kits. Results The plasma catestatin levels in CTO group were significantly higher than that in normal group (1.97±1.01 vs 1.36±0.97ng/ml, p = 0.009). In the CTO group, the patients with good collateral development had significantly higher catestatin and VEGF levels than those with poor collateral development (2.36±0.73 vs 1.61±1.12 ng/ml, p = 0.018; 425.23±140.10 vs 238.48±101.00pg/mL, p<0.001). There is a positive correlation between plasma catestatin levels and Rentrop scores (r = 0.40, p = 0.013) among the patients with CTO. However, there is no correlations between plasma catestatin levels and VEGF (r = -0.06, p = 0.744). In the multiple linear regression models, plasma catestatin level was one of the independent factors of coronary collateral development after adjustment for confounders. Conclusions Plasma catestatin was associated with coronary collateral developments. It may be a useful biomarker for coronary collateral development and potential target for therapeutic angiogenesis in patients with CTO.
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Affiliation(s)
- Weixian Xu
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
- * E-mail:
| | - Haiyi Yu
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
| | - Weihong Li
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
| | - Wei Gao
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
| | - Lijun Guo
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
| | - Guisong Wang
- Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China
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Halfdanarson TR, Howe JR, Haraldsdottir S, O'Dorisio TM. Circulating tumor markers in patients with neuroendocrine tumors – a clinical perspective. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.14.38] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract: Neuroendocrine tumors (NETs) are uncommon malignancies with a very diverse presentation and prognosis. Patients with NETs frequently have circulating tumor biomarkers that may aid in the diagnosis and help with prognostication. The most commonly used and best studied marker is chromogranin A, which appears to reflect the tumor burden and is useful at the time of diagnosis, and to monitor for recurrence after resection as well as to assess response to systemic therapy. Despite being the best studied marker, chromogranin A has significant limitations. Multiple other biomarkers are in use, but most have not been studied well and need further validation before being recommended for clinical practice. We review both established and novel circulating biomarkers, and highlight some of the limitations of tumor marker use in patients with NETs.
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Affiliation(s)
- Thorvardur R Halfdanarson
- Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center and Mayo Clinic Arizona, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA
| | - James R Howe
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | | | - Thomas M O'Dorisio
- Department of Internal Medicine, Division of Endocrinology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
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Herold Z, Nagy P, Patócs A, Somogyi A. [The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus]. Orv Hetil 2015; 156:163-170. [PMID: 25618857 DOI: 10.1556/oh.2015.30087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of β-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.
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Affiliation(s)
- Zoltán Herold
- Szent István Egyetem Állatorvos-tudományi Kar Budapest Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi utca 46. 1088
| | - Péter Nagy
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Patológiai és Kísérleti Rákkutató Intézet Budapest
| | - Attila Patócs
- Semmelweis Egyetem, Általános Orvostudományi Kar Laboratóriumi Medicina Intézet Budapest MTA-SE "Lendület" Örökletes Endokrin Daganatok Kutatócsoport Budapest
| | - Anikó Somogyi
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi utca 46. 1088
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Tota B, Angelone T, Cerra MC. The surging role of Chromogranin A in cardiovascular homeostasis. Front Chem 2014; 2:64. [PMID: 25177680 PMCID: PMC4132265 DOI: 10.3389/fchem.2014.00064] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
Together with Chromogranin B and Secretogranins, Chromogranin A (CGA) is stored in secretory (chromaffin) granules of the diffuse neuroendocrine system and released with noradrenalin and adrenalin. Co-stored within the granule together with neuropeptideY, cardiac natriuretic peptide hormones, several prohormones and their proteolytic enzymes, CGA is a multifunctional protein and a major marker of the sympatho-adrenal neuroendocrine activity. Due to its partial processing to several biologically active peptides, CGA appears an important pro-hormone implicated in relevant modulatory actions on endocrine, cardiovascular, metabolic, and immune systems through both direct and indirect sympatho-adrenergic interactions. As a part of this scenario, we here illustrate the emerging role exerted by the full-length CGA and its three derived fragments, i.e., Vasostatin 1, catestatin and serpinin, in the control of circulatory homeostasis with particular emphasis on their cardio-vascular actions under both physiological and physio-pathological conditions. The Vasostatin 1- and catestatin-induced cardiodepressive influences are achieved through anti-beta-adrenergic-NO-cGMP signaling, while serpinin acts like beta1-adrenergic agonist through AD-cAMP-independent NO signaling. On the whole, these actions contribute to widen our knowledge regarding the sympatho-chromaffin control of the cardiovascular system and its highly integrated “whip-brake” networks.
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Affiliation(s)
- Bruno Tota
- Department of Biology, Ecology and Earth Sciences, University of Calabria Arcavacata di Rende (CS), Italy
| | - Tommaso Angelone
- Department of Biology, Ecology and Earth Sciences, University of Calabria Arcavacata di Rende (CS), Italy
| | - Maria C Cerra
- Department of Biology, Ecology and Earth Sciences, University of Calabria Arcavacata di Rende (CS), Italy
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