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Kehr D, Ritterhoff J, Glaser M, Jarosch L, Salazar RE, Spaich K, Varadi K, Birkenstock J, Egger M, Gao E, Koch WJ, Sauter M, Freichel M, Katus HA, Frey N, Jungmann A, Busch C, Mather PJ, Ruhparwar A, Busch M, Völkers M, Wade RC, Most P. S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models. Circulation 2025; 151:548-565. [PMID: 39569500 PMCID: PMC11850016 DOI: 10.1161/circulationaha.123.066961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/15/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND The EF-hand Ca2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75-94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. METHODS We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models. RESULTS We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca2+ cycling and prevents β-adrenergic receptor-triggered Ca2+ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca2+ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. CONCLUSIONS S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.
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Affiliation(s)
- Dorothea Kehr
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
| | - Julia Ritterhoff
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
| | - Manuel Glaser
- Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.)
- Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany (M.G., R.C.W.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
| | - Lukas Jarosch
- Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.)
| | - Rafael E. Salazar
- Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.)
| | - Kristin Spaich
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
| | - Karl Varadi
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
| | - Jennifer Birkenstock
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
| | - Michael Egger
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
| | - Erhe Gao
- Center for Translational Medicine, Temple University, Philadelphia, PA (E.G.)
| | - Walter J. Koch
- Division of Cardiovascular and Thoracic Surgery, Duke University, Durham, NC (W.J.K.)
| | - Max Sauter
- Department of Clinical Pharmacology and Pharmacoepidemiology (M.S.), Heidelberg University Hospital (UKHD), Germany
| | - Marc Freichel
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
- Department of Pharmacology, Heidelberg Medical Faculty, Germany (M.F.)
| | - Hugo A. Katus
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
| | - Andreas Jungmann
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
| | - Cornelius Busch
- Department of Anesthesiology (C.B.), Heidelberg University Hospital (UKHD), Germany
| | - Paul J. Mather
- Perelman School of Medicine, University of Pennsylvania, Philadelphia (P.J.M.)
| | - Arjang Ruhparwar
- Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School, Hannover, Germany (A.R.)
| | - Martin Busch
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
| | - Mirko Völkers
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
| | - Rebecca C. Wade
- Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.)
- Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany (M.G., R.C.W.)
- Interdisciplinary Center for Scientific Computing (IWR), Heidelberg, Germany (R.C.W.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
| | - Patrick Most
- Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany
- Department of Cardiology, Angiology and Pneumology (D.K., J.R., K.S., K.V., J.B., M.E., H.A.K., N.F., A.J., M.B., M.V., P.M.), Heidelberg University Hospital (UKHD), Germany
- German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany (D.K., J.R., K.V., M.F., H.A.K., N.F., A.J., M.B., M.V., P.M.)
- Informatics for Life (I4L) consortium, Heidelberg, Germany (J.R., M.G., H.A.K., N.F., R.C.W., P.M.)
- Center for Translational Medicine, Jefferson University, Philadelphia, PA (P.M.)
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Liu Z, Wang J, Guo F, Xu T, Yu F, Deng Q, Tan W, Duan S, Song L, Wang Y, Sun J, Zhou L, Wang Y, Zhou X, Xia H, Jiang H. Role of S100β in Unstable Angina Pectoris: Insights from Quantitative Flow Ratio. Arch Med Res 2024; 55:103034. [PMID: 38972195 DOI: 10.1016/j.arcmed.2024.103034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND AND OBJECTIVE Disturbed autonomic nervous system (ANS) may promote inflammatory, immune, and oxidative stress responses, which may increase the risk of acute coronary events. S100β has been proposed as a biomarker of neuronal injury that would provide an insightful understanding of the crosstalk between the ANS, immune-inflammatory cells, and plaques that drive atherosclerosis. This study investigates the correlation between S100β, and functional coronary stenosis as determined by quantitative flow ratio (QFR). METHODS Patients with unstable angina pectoris (UAP) scheduled for coronary angiography and QFR were retrospectively enrolled. Serum S100β levels were determined by enzyme-linked immunosorbent assay. The Gensini score was used to estimate the extent of atherosclerotic lesions and the cumulative sum of three-vessel QFR (3V-QFR) was calculated to estimate the total atherosclerotic burden. RESULTS Two hundred thirty-three patients were included in this study. Receiver operator characteristic (ROC) curve indicated that S100β>33.28 pg/mL predicted functional ischemia in patients with UAP. Multivariate logistic analyses showed that a higher level of S100β was independently correlated with a functional ischemia-driven target vessel (QFR ≤0.8). This was also closely correlated with the severity of coronary lesions, as measured by the Gensini score (OR = 5.058, 95% CI: 2.912-8.793, p <0.001). According to 3V-QFR, S100β is inversely associated with total atherosclerosis burden (B = -0.002, p <0.001). CONCLUSIONS S100β was elevated in the functional ischemia stages of UAP. It was independently associated with coronary lesion severity as assessed by Gensini score and total atherosclerosis burden as estimated by 3V-QFR in patients with UAP.
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Affiliation(s)
- Zhihao Liu
- Department of Cardiology, Wuhan No.1 Hospital, Wuhan, Hubei, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Jun Wang
- Department of Cardiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Fuding Guo
- Department of Cardiology, Yan'an Hospital, Kunming Medical University, Kunming, China
| | - Tianyou Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Fu Yu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Qiang Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Wuping Tan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Shoupeng Duan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Lingpeng Song
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Yijun Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Ji Sun
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Liping Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Yueyi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Xiaoya Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, Wuhan, Hubei, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, Wuhan, Hubei, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China.
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Cao R, Zhang L, Zheng X. S-100β level is closely associated with myocardial work in patients with acute ischemic stroke. Int J Cardiol 2024; 400:131787. [PMID: 38242506 DOI: 10.1016/j.ijcard.2024.131787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/14/2024] [Indexed: 01/21/2024]
Abstract
BACKGROUND The more severe the acute stroke is, the more serious myocardial damage is. This study aimed to determine the relationship between myocardial work and S100β, a quantitative biomarker of active cerebral lesions, in patients with acute ischemic stroke (AIS). METHODS A total of 63 patients with AIS were examined by myocardial work echocardiography, 4D echocardiography with the measurement of left ventricular (LV) myocardial work, volume and function within 24-48 h of symptom onset, respectively. Their plasma S100β was measured from a peripheral blood sample within 2-6 h of symptom onset. RESULTS Patients with elevated S-100β level had significantly increased ratios of peak early diastolic transmitral filling velocity to peak early diastolic lateral mitral annulus tissue velocity(E/e') and global longitudinal strain (GLS), and significantly reduced global work index(GWI) and global constructive work (GCW) compared with those with normal S-100β level (p < 0.05). S-100β positively correlated with E/e'(r = 0.878, p < 0.0001) and GLS (r = 0.511, p = 0.002) but negatively correlated with GWI(r = -0.409, p = 0.034) and GCW(r = -0.353, p = 0.041). S-100β showed an excellent ability to differentiate if a reduced GWI [cut-off value, 120.79 pg/mL; area under receiver operating characteristic curve (AUC), 1.000; sensitivity, 100%; specificity, 100%], GCW (cut-off value, 120.79 pg/mL;AUC,1.000; sensitivity,100%; specificity, 100%) and an increased E/e' (cut-off value, 91.1 pg/mL;AUC,0.913; sensitivity,80%; specificity, 100%) or not, but poor ability to differentiate if an increased GLS(cut-off value, 91.1 pg/mL; AUC,0.576; sensitivity,63.64%; specificity, 83.33%) or not. CONCLUSION S-100β level is closely associated with LV function. It is highly competent in determining an impaired myocardial work in patients with AIS.
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Affiliation(s)
- Ran Cao
- Department of Ultrasound, Fuding Hospital Fujian Province/Fuding Hospital Affiliated to Fujian University of Traditional Chinese Medicine, 120 South Gucheng Road, Fuding City 355200, Fujian Province, People's Republic of China
| | - Lijuan Zhang
- Department of Ultrasound, The Fourth Affiliated Hospital of Nanjing Medical University, 298 Nanpu Road, Jiangbei New Area, Nanjing 210031, Jiangsu Province, People's Republic of China
| | - Xiaozhi Zheng
- Department of Ultrasound, Yangpu Hospital, School of Medicine, Tongji University, 450 Tengyue Road, Shanghai 200090, People's Republic of China.
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Ding S, Wang C, Wang W, Yu H, Chen B, Liu L, Zhang M, Lang Y. Autocrine S100B in astrocytes promotes VEGF-dependent inflammation and oxidative stress and causes impaired neuroprotection. Cell Biol Toxicol 2023; 39:1-25. [PMID: 34792689 DOI: 10.1007/s10565-021-09674-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/11/2021] [Indexed: 12/20/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.
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Affiliation(s)
- Saidan Ding
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Chengde Wang
- Neurosurgery department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Weikan Wang
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - He Yu
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Baihui Chen
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Leping Liu
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Minxue Zhang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yan Lang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
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5
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Zhou Y, Zha Y, Yang Y, Ma T, Li H, Liang J. S100 proteins in cardiovascular diseases. Mol Med 2023; 29:68. [PMID: 37217870 DOI: 10.1186/s10020-023-00662-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 05/02/2023] [Indexed: 05/24/2023] Open
Abstract
Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.
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Affiliation(s)
- Yue Zhou
- Medical College, Yangzhou University, Yangzhou, China
| | - Yiwen Zha
- Medical College, Yangzhou University, Yangzhou, China
| | - Yongqi Yang
- Medical College, Yangzhou University, Yangzhou, China
| | - Tan Ma
- Medical College, Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Hongliang Li
- Medical College, Yangzhou University, Yangzhou, China.
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
| | - Jingyan Liang
- Medical College, Yangzhou University, Yangzhou, China.
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China.
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6
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Chasovskikh NY, Chizhik EE, Bobrysheva AA. Bioinformatic Annotation of Genes for Alzheimer’s Disease and Coronary Heart Disease. RUSS J GENET+ 2021. [DOI: 10.1134/s102279542111003x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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7
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Biomarkers Utility: At the Borderline between Cardiology and Neurology. J Cardiovasc Dev Dis 2021; 8:jcdd8110139. [PMID: 34821692 PMCID: PMC8621331 DOI: 10.3390/jcdd8110139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 12/21/2022] Open
Abstract
Biomarkers are important diagnostic and prognostic tools as they provide results in a short time while still being an inexpensive, reproducible and accessible method. Their well-known benefits have placed them at the forefront of research in recent years, with new and innovative discoveries being implemented. Cardiovascular and neurological diseases often share common risk factors and pathological pathways which may play an important role in the use and interpretation of biomarkers' values. Among the biomarkers used extensively in clinical practice in cardiology, hs-TroponinT, CK-MB and NTproBNP have been shown to be strongly influenced by multiple neurological conditions. Newer ones such as galectin-3, lysophosphatidylcholine, copeptin, sST2, S100B, myeloperoxidase and GDF-15 have been extensively studied in recent years as alternatives with an increased sensitivity for cardiovascular diseases, but also with significant results in the field of neurology. Thus, given their low specificity, the values interpretation must be correlated with the clinical judgment and other available investigations.
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8
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Kim HD, Karna S, Shin Y, Vu H, Cho HJ, Kim S. S100A8 and S100A9 in saliva, blood and gingival crevicular fluid for screening established periodontitis: a cross-sectional study. BMC Oral Health 2021; 21:388. [PMID: 34372836 PMCID: PMC8351418 DOI: 10.1186/s12903-021-01749-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 07/19/2021] [Indexed: 12/31/2022] Open
Abstract
Background Periodontitis is one of major oral diseases, which has no consensus on early screening tool. This study aimed to compare the association and screening ability of S100A8 and S100A9 in saliva, blood and gingival crevicular fluid (GCF) for periodontitis status. Methods We recruited 149 community Korean adults, 50 no or initial periodontitis (NIPERIO) and 99 established periodontitis (PERIO). Using clinical attachment loss and a panoramic radiograph, stage II–IV of new classification of periodontitis proposed at 2018 was considered cases as PERIO. Enzyme linked immunosorbent assay kit was used to quantify S100A8 and S100A9. T-test, analysis of covariance, Mann–Whitney test and correlation analysis were applied to compare the relationship of S100A8 and S100A9 in saliva, blood, and GCF for periodontitis. Receiver operating characteristic curve was applied for screening ability. Results Among S100A8 and S100A9 in saliva, blood and GCF, S100A8 in saliva was significantly higher in PERIO than in NIPERIO (p < 0.05). However, S100A8 and S100A9 in GCF were higher in NIPERIO (p < 0.05). The screening ability of salivary S100A8 was 75% for PERIO, while that of GCF S100A8 was 74% for NIPERIO. Salivary S100A8 was positively correlated to blood S100A8 (p < 0.05). Conclusion Salivary S100A8 could be a potential diagnostic marker for established periodontitis and be useful for screening established periodontitis. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-021-01749-z.
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Affiliation(s)
- Hyun-Duck Kim
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Dental Research Institute, Seoul National University, Seoul, Korea.
| | - Sandeep Karna
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - YooJin Shin
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Huong Vu
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Hyun-Jae Cho
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Dental Research Institute, Seoul National University, Seoul, Korea
| | - Sungtae Kim
- Dental Research Institute, Seoul National University, Seoul, Korea.,Department of Periodontology, Seoul National University Dental Hospital, Seoul, Korea
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9
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Michetti F, Di Sante G, Clementi ME, Sampaolese B, Casalbore P, Volonté C, Romano Spica V, Parnigotto PP, Di Liddo R, Amadio S, Ria F. Growing role of S100B protein as a putative therapeutic target for neurological- and nonneurological-disorders. Neurosci Biobehav Rev 2021; 127:446-458. [PMID: 33971224 DOI: 10.1016/j.neubiorev.2021.04.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/15/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
S100B is a calcium-binding protein mainly expressed by astrocytes, but also localized in other definite neural and extra-neural cell types. While its presence in biological fluids is widely recognized as a reliable biomarker of active injury, growing evidence now indicates that high levels of S100B are suggestive of pathogenic processes in different neural, but also extra-neural, disorders. Indeed, modulation of S100B levels correlates with the occurrence of clinical and/or toxic parameters in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, acute neural injury, inflammatory bowel disease, uveal and retinal disorders, obesity, diabetes and cancer, thus directly linking the levels of S100B to pathogenic mechanisms. In general, deletion/inactivation of the protein causes the improvement of the disease, whereas its over-expression/administration induces a worse clinical presentation. This scenario reasonably proposes S100B as a common therapeutic target for several different disorders, also offering new clues to individuate possible unexpected connections among these diseases.
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Affiliation(s)
- Fabrizio Michetti
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; IRCCS San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, 20132 Milan, Italy.
| | - Gabriele Di Sante
- Department of Translational Medicine and Surgery, Section of General Pathology, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 1-8, 00168 Rome, Italy.
| | - Maria Elisabetta Clementi
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" SCITEC-CNR, Largo Francesco Vito 1, 00168 Rome, Italy.
| | - Beatrice Sampaolese
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" SCITEC-CNR, Largo Francesco Vito 1, 00168 Rome, Italy.
| | - Patrizia Casalbore
- Institute for Systems Analysis and Computer Science, IASI-CNR, Largo Francesco Vito 1, 00168 Rome, Italy.
| | - Cinzia Volonté
- Institute for Systems Analysis and Computer Science, IASI-CNR, Largo Francesco Vito 1, 00168 Rome, Italy; Cellular Neurobiology Unit, Preclinical Neuroscience, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 65, 00143 Rome, Italy.
| | - Vincenzo Romano Spica
- Department of Movement, Human and Health Sciences, Laboratory of Epidemiology and Biotechnologies, University of Rome "Foro Italico", Piazza Lauro De Bosis 6, 00135, Rome, Italy.
| | - Pier Paolo Parnigotto
- Foundation for Biology and Regenerative Medicine, Tissue Engineering and Signaling (T.E.S.) Onlus, Padua, Italy.
| | - Rosa Di Liddo
- Foundation for Biology and Regenerative Medicine, Tissue Engineering and Signaling (T.E.S.) Onlus, Padua, Italy; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Italy.
| | - Susanna Amadio
- Cellular Neurobiology Unit, Preclinical Neuroscience, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 65, 00143 Rome, Italy.
| | - Francesco Ria
- Department of Translational Medicine and Surgery, Section of General Pathology, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 1-8, 00168 Rome, Italy.
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10
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Sharif AF, Elsheikh E, Al-Asmari AZ, Gameel DE. Potential Role of Serum S-100β Protein as a Predictor of Cardiotoxicity and Clinical Poor Outcome in Acute Amphetamine Intoxication. Cardiovasc Toxicol 2021; 21:375-386. [PMID: 33423174 DOI: 10.1007/s12012-020-09630-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/29/2020] [Indexed: 11/28/2022]
Abstract
Cardio- and neurotoxicity of amphetamines play an important role in worsening morbidity, making the initial evaluation of the patient's status a potentially lifesaving action. The current study hypothesized that the S-100β serum level could predict the severity of acute amphetamine toxicity and the in-hospital outcome. The current study is a prospective cohort study conducted on 77 patients diagnosed with acute amphetamine exposure and referred to Aseer Poison Control Center, Saudi Arabia. The patients admitted to ICU showed significantly higher serum levels of S-100β in comparison to those not admitted (p < 0.05). Moreover, the S-100β level was significantly elevated among patients with prolonged QTc intervals. Receiver-operating characteristic curve of S-100β serum level as an in-hospital outcome predictor showed that at a cutoff value > 0.430 ug/L, the sensitivity of S-100β serum level as severity predictor was 100%, and the specificity was 74.1%. In conclusion, the current study revealed that the S-100β serum level could be used as an outcome predictor in hospital admission cases due to toxic amphetamine exposure and offers an idea about the cardiac and neuronal involvement. This can help select patients who will benefit most from ICU admission and early management and assess the severity of cases in settings where GC-MS is not available.
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Affiliation(s)
- Asmaa F Sharif
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. .,Clinical Sciences Departement, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia.
| | - Eman Elsheikh
- Cardiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.,Internal Medicine Department, King Faisal University, Hofuf, Saudi Arabia
| | - Abdullah Z Al-Asmari
- Poison Control Centers and Medical Chemistry Legitimacy South, Aseer, Saudi Arabia.,Poison Control Center, Aseer, Saudi Arabia
| | - Dina El Gameel
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.,Poison Control Center, Aseer, Saudi Arabia
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11
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Kim HD, Kim S, Jeon S, Kim SJ, Cho HJ, Choi YN. Diagnostic and Prognostic ability of salivary MMP-9 and S100A8 for periodontitis. J Clin Periodontol 2020; 47:1191-1200. [PMID: 32744384 DOI: 10.1111/jcpe.13349] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Salivary diagnostic using matrix metalloproteinase (MMP) and S100 for periodontitis is a promising issue. However, its prognostic effect is still unclear. This study aimed to evaluate the prognostic ability of salivary MMP-9 and S100A8 for periodontitis through non-surgical periodontitis treatment clinical trial. MATERIALS AND METHODS Total 149 participants, 99 periodontitis and 50 healthy, were recruited. Among 99 non-surgical periodontitis treatment participants, 74 participants were revisited after three months. Periodontitis was classified as stage II-IV of new classification of periodontitis proposed at 2018. Enzyme-linked immunosorbent assay kit was used to quantify salivary MMP-9 and S100A8. Receiver operating characteristic curve was applied for diagnostic ability. Paired t test was applied for prognostic ability evaluating changes in salivary markers between pre- and post-treatment. RESULTS Salivary MMP-9 and S100A8 were associated with periodontitis (p < .05). The screening ability of algorithm using salivary MMP-9 and S100A8 for periodontitis was 0.86 (p < .05). After treatment, reduction rate of salivary S100A8 and MMP-9 was 83.7% and 23.5%, respectively, (p < .05): only salivary S100A8 was superior compared to clinical parameters. CONCLUSION Algorithm using salivary MMP-9 and S100A8 showed high diagnostic power for periodontitis. Both salivary S100A8 and MMP-9 showed prognostic ability for periodontitis, but S100A8 was better.
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Affiliation(s)
- Hyun-Duck Kim
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, Seoul, Korea.,Dental Research Institute, Seoul National University, Seoul, Korea
| | - Sungtae Kim
- Department of Periodontology, Seoul National University Dental Hospital, Seoul, Korea
| | - Sumin Jeon
- Department of Microbiology and Immunity, School of Dentistry, Seoul National University, Seoul, Korea
| | - Seon-Jip Kim
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, Seoul, Korea
| | - Hyun-Jae Cho
- Department of Preventive and Social Dentistry, School of Dentistry, Seoul National University, Seoul, Korea.,Dental Research Institute, Seoul National University, Seoul, Korea
| | - Young-Nim Choi
- Dental Research Institute, Seoul National University, Seoul, Korea.,Department of Microbiology and Immunity, School of Dentistry, Seoul National University, Seoul, Korea
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12
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Chen Y, Chen X, Yao M, Chen L, Chen W, Liu X. Association of S100B 3'UTR polymorphism with risk of chronic heart failure in a Chinese Han population. Medicine (Baltimore) 2020; 99:e21018. [PMID: 32590820 PMCID: PMC7328937 DOI: 10.1097/md.0000000000021018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
To study the correlation between single nucleotide polymorphism (SNP) of the 3' untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84-6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.
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Affiliation(s)
| | - Xianghong Chen
- Department of General Medicine, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road
| | - Maozhong Yao
- Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou, Hainan Province, China
| | - Lei Chen
- Department of Cardiovascular Medicine
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13
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Baudier J, Deloulme JC, Shaw GS. The Zn 2+ and Ca 2+ -binding S100B and S100A1 proteins: beyond the myths. Biol Rev Camb Philos Soc 2020; 95:738-758. [PMID: 32027773 DOI: 10.1111/brv.12585] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 01/06/2020] [Accepted: 01/20/2020] [Indexed: 12/17/2022]
Abstract
The S100 genes encode a conserved group of 21 vertebrate-specific EF-hand calcium-binding proteins. Since their discovery in 1965, S100 proteins have remained enigmatic in terms of their cellular functions. In this review, we summarize the calcium- and zinc-binding properties of the dimeric S100B and S100A1 proteins and highlight data that shed new light on the extracellular and intracellular regulation and functions of S100B. We point out that S100B and S100A1 homodimers are not functionally interchangeable and that in a S100A1/S100B heterodimer, S100A1 acts as a negative regulator for the ability of S100B to bind Zn2+ . The Ca2+ and Zn2+ -dependent interactions of S100B with a wide array of proteins form the basis of its activities and have led to the derivation of some initial rules for S100B recognition of protein targets. However, recent findings have strongly suggested that these rules need to be revisited. Here, we describe a new consensus S100B binding motif present in intracellular and extracellular vertebrate-specific proteins and propose a new model for stable interactions of S100B dimers with full-length target proteins. A chaperone-associated function for intracellular S100B in adaptive cellular stress responses is also discussed. This review may help guide future studies on the functions of S100 proteins in general.
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Affiliation(s)
- Jacques Baudier
- Institut de Biologie du Développement de Marseille-UMR CNRS 7288, Aix Marseille Université, 13288, Marseille Cedex 9, France
| | - Jean Christophe Deloulme
- Grenoble Institut des Neurosciences, INSERM U1216, Université Grenoble Alpes, 38000, Grenoble, France
| | - Gary S Shaw
- Department of Biochemistry, University of Western Ontario, London, Ontario, N6A5C1, Canada
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14
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Sreejit G, Flynn MC, Patil M, Krishnamurthy P, Murphy AJ, Nagareddy PR. S100 family proteins in inflammation and beyond. Adv Clin Chem 2020; 98:173-231. [PMID: 32564786 DOI: 10.1016/bs.acc.2020.02.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases. Strategies aimed at targeting S100-mediated signaling pathways hold a great potential in developing novel therapeutics for multiple diseases. In this chapter, we aim to summarize the current knowledge about the role of S100 family proteins in health and disease with a major focus on their role in inflammatory conditions.
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Affiliation(s)
| | - Michelle C Flynn
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Mallikarjun Patil
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Department of Immunology, Monash University, Melbourne, VIC, Australia
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15
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Zhang P, Li YX, Zhang ZZ, Yang Y, Rao JX, Xia L, Li XY, Chen GH, Wang F. Astroglial Mechanisms Underlying Chronic Insomnia Disorder: A Clinical Study. Nat Sci Sleep 2020; 12:693-704. [PMID: 33117005 PMCID: PMC7549496 DOI: 10.2147/nss.s263528] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/27/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The objective of this study was to investigate whether the serum biomarkers S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) change in patients with chronic insomnia disorder (CID), and if this is the case, whether the altered levels of these serum biomarkers are associated with poor sleep quality and cognitive decline in CID. PATIENTS AND METHODS Fifty-seven CID outpatients constituted the CID group; thirty healthy controls (HC) were also enrolled. Questionnaires, polysomnography, Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test (NBMT) were used to assess their sleep and neuropsychological function. Serum S100B, GFAP, BDNF, and GDNF were evaluated using enzyme-linked immunosorbent assay. RESULTS The CID group had higher levels of S100B and GFAP and lower levels of BDNF and GDNF than the HC group. Spearman correlation analysis revealed that poor sleep quality, assessed by subjective and objective measures, was positively correlated with S100B level and negatively correlated with BDNF level. GFAP level correlated positively with poor subjective sleep quality. Moreover, S100B and GFAP levels correlated negatively with general cognitive function assessed using MoCA-C. GFAP level correlated positively with poor spatial working memory (SWM) in the NBMT; BDNF level was linked to poor SWM and object recognition memory (ORcM) in the NBMT. However, principal component analysis revealed that serum S100B level was positively linked to the errors in object working memories, BDNF and GDNF concentrations were negatively linked with errors in ORcM, and GFAP concentration was positively correlated with the errors in the SWM and spatial reference memories. CONCLUSION Serum S100B, GFAP, BDNF, and GDNF levels were altered in patients with CID, indicating astrocyte damage, and were associated with insomnia severity or/and cognitive dysfunction.
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Affiliation(s)
- Ping Zhang
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Ying-Xue Li
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Zhe-Zhe Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Ye Yang
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Ji-Xian Rao
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Lan Xia
- Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, People's Republic of China
| | - Xue-Yan Li
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Gui-Hai Chen
- Department of Sleep Disorders, The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, People's Republic of China
| | - Fang Wang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
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16
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Riuzzi F, Chiappalupi S, Arcuri C, Giambanco I, Sorci G, Donato R. S100 proteins in obesity: liaisons dangereuses. Cell Mol Life Sci 2020; 77:129-147. [PMID: 31363816 PMCID: PMC11104817 DOI: 10.1007/s00018-019-03257-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 07/19/2019] [Accepted: 07/24/2019] [Indexed: 02/07/2023]
Abstract
Obesity is an endemic pathophysiological condition and a comorbidity associated with hypercholesterolemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and cancer. The adipose tissue of obese subjects shows hypertrophic adipocytes, adipocyte hyperplasia, and chronic low-grade inflammation. S100 proteins are Ca2+-binding proteins exclusively expressed in vertebrates in a cell-specific manner. They have been implicated in the regulation of a variety of functions acting as intracellular Ca2+ sensors transducing the Ca2+ signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors. Certain S100 proteins, namely S100A4, the S100A8/S100A9 heterodimer and S100B, have been implicated in the pathophysiology of obesity-promoting macrophage-based inflammation via toll-like receptor 4 and/or receptor for advanced glycation end-products ligation. Also, serum levels of S100A4, S100A8/S100A9, S100A12, and S100B correlate with insulin resistance/type 2 diabetes, metabolic risk score, and fat cell size. Yet, secreted S100B appears to exert neurotrophic effects on sympathetic fibers in brown adipose tissue contributing to the larger sympathetic innervation of this latter relative to white adipose tissue. In the present review we first briefly introduce S100 proteins and then critically examine their role(s) in adipose tissue and obesity.
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Affiliation(s)
- Francesca Riuzzi
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
| | - Sara Chiappalupi
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
| | - Cataldo Arcuri
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Guglielmo Sorci
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale, University of Perugia, 06132, Perugia, Italy
| | - Rosario Donato
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
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Heizmann CW. S100 proteins: Diagnostic and prognostic biomarkers in laboratory medicine. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1197-1206. [DOI: 10.1016/j.bbamcr.2018.10.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/12/2018] [Indexed: 01/04/2023]
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Heizmann CW. Ca 2+-Binding Proteins of the EF-Hand Superfamily: Diagnostic and Prognostic Biomarkers and Novel Therapeutic Targets. Methods Mol Biol 2019; 1929:157-186. [PMID: 30710273 DOI: 10.1007/978-1-4939-9030-6_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A multitude of Ca2+-sensor proteins containing the specific Ca2+-binding motif (helix-loop-helix, called EF-hand) are of major clinical relevance in a many human diseases. Measurements of troponin, the first intracellular Ca-sensor protein to be discovered, is nowadays the "gold standard" in the diagnosis of patients with acute coronary syndrome (ACS). Mutations have been identified in calmodulin and linked to inherited ventricular tachycardia and in patients affected by severe cardiac arrhythmias. Parvalbumin, when introduced into the diseased heart by gene therapy to increase contraction and relaxation speed, is considered to be a novel therapeutic strategy to combat heart failure. S100 proteins, the largest subgroup with the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation, and autoimmune pathologies. The intention of this review is to summarize the clinical importance of this protein family and their use as biomarkers and potential drug targets, which could help to improve the diagnosis of human diseases and identification of more selective therapeutic interventions.
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Affiliation(s)
- Claus W Heizmann
- Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zürich, Zürich, Switzerland.
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19
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Riuzzi F, Sorci G, Arcuri C, Giambanco I, Bellezza I, Minelli A, Donato R. Cellular and molecular mechanisms of sarcopenia: the S100B perspective. J Cachexia Sarcopenia Muscle 2018; 9:1255-1268. [PMID: 30499235 PMCID: PMC6351675 DOI: 10.1002/jcsm.12363] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 09/27/2018] [Indexed: 12/11/2022] Open
Abstract
Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca2+ -sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast-brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia.
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Affiliation(s)
- Francesca Riuzzi
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.,Interuniversity Institute of Myology
| | - Guglielmo Sorci
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.,Interuniversity Institute of Myology
| | - Cataldo Arcuri
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.,Interuniversity Institute of Myology
| | - Ileana Giambanco
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.,Interuniversity Institute of Myology
| | - Ilaria Bellezza
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Alba Minelli
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Rosario Donato
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.,Interuniversity Institute of Myology.,Centro Universitario di Ricerca sulla Genomica Funzionale, University of Perugia, Perugia, 06132, Italy
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20
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Donato R, Sorci G, Giambanco I. S100A6 protein: functional roles. Cell Mol Life Sci 2017; 74:2749-2760. [PMID: 28417162 PMCID: PMC11107720 DOI: 10.1007/s00018-017-2526-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 02/24/2017] [Accepted: 02/27/2017] [Indexed: 12/20/2022]
Abstract
S100A6 protein belongs to the A group of the S100 protein family of Ca2+-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6's effects. Dosage of serum S100A6 might aid in diagnosis in oncology.
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Affiliation(s)
- Rosario Donato
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
- Department of Experimental Medicine, Istituto Interuniversitario di Miologia (Interuniversity Institute for Myology), Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
| | - Guglielmo Sorci
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Department of Experimental Medicine, Istituto Interuniversitario di Miologia (Interuniversity Institute for Myology), Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
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21
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S100B raises the alert in subarachnoid hemorrhage. Rev Neurosci 2016; 27:745-759. [DOI: 10.1515/revneuro-2016-0021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 05/26/2016] [Indexed: 12/19/2022]
Abstract
AbstractSubarachnoid hemorrhage (SAH) is a devastating disease with high mortality and mobility, the novel therapeutic strategies of which are essentially required. The calcium binding protein S100B has emerged as a brain injury biomarker that is implicated in pathogenic process of SAH. S100B is mainly expressed in astrocytes of the central nervous system and functions through initiating intracellular signaling or via interacting with cell surface receptor, such as the receptor of advanced glycation end products. The biological roles of S100B in neurons have been closely associated with its concentrations, resulting in either neuroprotection or neurotoxicity. The levels of S100B in the blood have been suggested as a biomarker to predict the progress or the prognosis of SAH. The role of S100B in the development of cerebral vasospasm and brain damage may result from the induction of oxidative stress and neuroinflammation after SAH. To get further insight into mechanisms underlying the role of S100B in SAH based on this review might help us to find novel therapeutic targets for SAH.
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22
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Adipokines and their receptors: potential new targets in cardiovascular diseases. Future Med Chem 2015; 7:139-57. [PMID: 25686003 DOI: 10.4155/fmc.14.147] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is an 'endocrine organ' that influences diverse physiological and pathological processes via adipokines secretion. Strong evidences suggest that epicardial and perivascular adipose tissue can directly regulate heart and vessels' structure and function. Indeed, in obesity there is a shift toward the secretion of adipokines that promote a pro-inflammatory status and contribute to obesity cardiomyopathy. The prospect of modulating adipokines and/or their receptors represents an attractive perspective to the treatment of cardiovascular diseases. In this paper, we described the most important actions of certain adipokines and their receptors that are capable of influencing cardiovascular physiology as well as their possible use as therapeutic targets.
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23
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Serpero LD, Pluchinotta F, Gazzolo D. The clinical and diagnostic utility of S100B in preterm newborns. Clin Chim Acta 2015; 444:193-198. [PMID: 25704302 DOI: 10.1016/j.cca.2015.02.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 02/06/2015] [Accepted: 02/14/2015] [Indexed: 11/18/2022]
Abstract
Preterm birth is still the most important cause of perinatal mortality and morbidity. Follow-up studies showed that the majority of neurological abnormalities during childhood are already present in the first week after birth. In this light, the knowledge of the timing of the insult and/or of the contributing factors is of utmost relevance in order to avoid adverse neurological outcome. Notwithstanding, the considerable advances in perinatal clinical care and monitoring, the early detection of cases at risk for brain damage is still a challenge because, when radiological pictures are still negative, brain damage may be already at a subclinical stage, with symptoms hidden by therapeutic strategies. Thus, it could be very relevant to measure quantitative parameters, such as neuroproteins, able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent. In the last decade, the assay of the brain-specific protein S100B in different biological fluids proved useful information on brain function and damage in the perinatal period. Therefore, the present study provides an overview of the most recent findings on S100B role as a reliable marker of brain development/damage in preterm high risk fetuses and newborns.
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Affiliation(s)
- Laura D Serpero
- Dept. of Maternal Fetal and Neonatal Medicine C. Arrigo Children's Hospital, Alessandria, Italy
| | - Francesca Pluchinotta
- Dept. of Pediatric Cardiovascular Surgery, IRCCS San Donato Milanese Hospital, San Donato Milanese, Italy
| | - Diego Gazzolo
- Dept. of Maternal Fetal and Neonatal Medicine C. Arrigo Children's Hospital, Alessandria, Italy.
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Yannarelli G, Tsoporis JN, Desjardins JF, Wang XH, Pourdjabbar A, Viswanathan S, Parker TG, Keating A. Donor mesenchymal stromal cells (MSCs) undergo variable cardiac reprogramming in vivo and predominantly co-express cardiac and stromal determinants after experimental acute myocardial infarction. Stem Cell Rev Rep 2014; 10:304-15. [PMID: 24287730 DOI: 10.1007/s12015-013-9483-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We previously showed the emergence of predominantly non-fused murine cells co-expressing cardiac and stromal determinants in co-cultures of murine mesenchymal stromal cells (MSCs) and rat embryonic cardiomyocytes. To determine whether a similar phenotype is detectable in vivo in ischemic myocardium, we infused green fluorescence protein (GFP)-marked MSCs intravenously into wild-type mice in an acute myocardial infarction (AMI) model generated by ischemia/reperfusion (I/R) or fixed coronary artery ligation. We found that infused GFP+ cells were confined strictly to ischemic areas and represented approximately 10% of total cellularity. We showed that over 60% of the cells co-expressed collagen type IV and troponin T or myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Nonetheless, up to 25% of the GFP+ donor cells expressed one of two cardiomyocyte markers, either myosin heavy chain or troponin T, in the absence of MSC determinants. We also observed a marked reduction in OCT4 expression in MSCs pre-infusion compared with those lodged in the myocardium, suggesting reduced stem cell properties. Despite the low frequency of lodged donor MSCs, left-ventricular end-diastolic pressure was significantly better in experimental versus saline animals for both AMI (12.10 ± 1.81 vs. 20.50 ± 1.53 mmHg, p < 0.001) and I/R models (8.75 ± 2.95 vs. 17.53 ± 3.85 mmHg, p = 0.004) when measured 21 days after MSC infusion and is consistent with a paracrine effect. Our data indicate that donor MSCs undergo variable degrees of cardiomyocyte reprogramming with the majority co-expressing cardiomyocyte and stromal markers. Further studies are needed to elucidate the factors mediating the extent of cardiomyocyte reprogramming and importance of the cellular changes on tissue repair.
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Affiliation(s)
- Gustavo Yannarelli
- Cell Therapy Program, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Ave, Suite 5-303, Toronto, ON, Canada, M5G 2M9
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Liyanage VRB, Zachariah RM, Rastegar M. Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells. Mol Autism 2013; 4:46. [PMID: 24238559 PMCID: PMC3900258 DOI: 10.1186/2040-2392-4-46] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 10/01/2013] [Indexed: 01/01/2023] Open
Abstract
Background Aberrant MeCP2 expression in brain is associated with neurodevelopmental disorders including autism. In the brain of stressed mouse and autistic human patients, reduced MeCP2 expression is correlated with Mecp2/MECP2 promoter hypermethylation. Altered expression of MeCP2 isoforms (MeCP2E1 and MeCP2E2) is associated with neurological disorders, highlighting the importance of proper regulation of both isoforms. While known regulatory elements (REs) within the MECP2/Mecp2 promoter and intron 1 are involved in MECP2/Mecp2 regulation, Mecp2 isoform-specific regulatory mechanisms are unknown. We hypothesized that DNA methylation at these REs may impact the expression of Mecp2 isoforms. Methods We used a previously characterized in vitro differentiating neural stem cell (NSC) system to investigate the interplay between Mecp2 isoform-specific expression and DNA methylation at the Mecp2 REs. We studied altered expression of Mecp2 isoforms, affected by global DNA demethylation and remethylation, induced by exposure and withdrawal of decitabine (5-Aza-2′-deoxycytidine). Further, we performed correlation analysis between DNA methylation at the Mecp2 REs and the expression of Mecp2 isoforms after decitabine exposure and withdrawal. Results At different stages of NSC differentiation, Mecp2 isoforms showed reciprocal expression patterns associated with minor, but significant changes in DNA methylation at the Mecp2 REs. Decitabine treatment induced Mecp2e1/MeCP2E1 (but not Mecp2e2) expression at day (D) 2, associated with DNA demethylation at the Mecp2 REs. In contrast, decitabine withdrawal downregulated both Mecp2 isoforms to different extents at D8, without affecting DNA methylation at the Mecp2 REs. NSC cell fate commitment was minimally affected by decitabine under tested conditions. Expression of both isoforms negatively correlated with methylation at specific regions of the Mecp2 promoter, both at D2 and D8. The correlation between intron 1 methylation and Mecp2e1 (but not Mecp2e2) varied depending on the stage of NSC differentiation (D2: negative; D8: positive). Conclusions Our results show the correlation between the expression of Mecp2 isoforms and DNA methylation in differentiating NSC, providing insights on the potential role of DNA methylation at the Mecp2 REs in Mecp2 isoform-specific expression. The ability of decitabine to induce Mecp2e1/MeCP2E1, but not Mecp2e2 suggests differential sensitivity of Mecp2 isoforms to decitabine and is important for future drug therapies for autism.
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Affiliation(s)
| | | | - Mojgan Rastegar
- Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Rm, 627, Basic Medical Sciences Bldg,, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada.
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26
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Faa A, Xanthos T, Papalois A, Locci A, Pampaloni P, Pais ME, Aroni F, Gazzolo D, Faa G, Iacovidou N. S100B immunoreactivity: a new marker of hypoxia-related cardiac damage in newborn piglets. J Matern Fetal Neonatal Med 2013; 26 Suppl 2:72-76. [PMID: 24059558 DOI: 10.3109/14767058.2013.830410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The evaluation of the expression of S100B protein, in the swine heart in an experimental model of hypoxia - reoxygenation. METHODS Normocapnic hypoxia was induced in 40 male Landrace/Large White neonatal piglets by decreasing the inspired concentration of oxygen to 6-8%. When animals developed bradycardia or severe hypotension, reoxygenation was initiated. Piglets were allocated in four groups of 10, according to the oxygen concentration they were reoxygenated with: Group 1, 2, 3 and 4 resuscitated with 18%, 21%, 40% and 100% oxygen, respectively. The animals were further classified into 4 groups according with the time required for reoxygenation: group A (<15 min); group B (16-60 min); group C (>60 min); group D (deceased animals). RESULTS Immunostaining for S100B protein was detected in 14 out of the 40 heart samples (35%), both inside the cytoplasm of cardiomyocytes and as globular deposits in the interstitial spaces. Significant differences were observed among groups 1-4 regarding S100B expression. Reactivity for S100B in cardiac cells was detected in 50%, 50%, 10% and 33% of animals in groups 1 and 2, 3 and 4, respectively. Marked differences were also observed among groups A-D: 75%, 33%, 12% and 22% of the animals in group 1, 2, 3 and 4, respectively, showed reactivity for S100B in the heart. CONCLUSIONS Expression of S100B protein occurred in the heart of some of newborn piglets following severe hypoxia. S100B storage in cardiomyocytes correlates with the different oxygen concentration used during reoxygenation, being higher in piglets reoxygenated with 18% and 21%, and lower in animals reoxygenated with 40% oxygen. Intermediate levels of S100B expression were found in 100% O2-treated animals. The finding of a higher percentage of S100B-immunoreactive hearts in piglets with a fast recovery and the detection of a decreased reactivity in animals with a slow and a very slow recovery clearly indicates S100B protein as an early protective factor with a positive prognostic value in asphyxiated newborn piglets.
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Affiliation(s)
- Armando Faa
- Department of Pathology, University of Cagliari , Cagliari , Italy
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Abstract
The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.
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Affiliation(s)
- R Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
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Kumar P, Raghavan S, Shanmugam G, Shanmugam N. Ligation of RAGE with ligand S100B attenuates ABCA1 expression in monocytes. Metabolism 2013; 62:1149-58. [PMID: 23523156 DOI: 10.1016/j.metabol.2013.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 02/04/2013] [Accepted: 02/19/2013] [Indexed: 01/17/2023]
Abstract
HYPOTHESIS ATP Binding Cassette Transporter (ABC) A1 is one of the key regulators of HDL synthesis and reverse cholesterol transport. Activation of Receptors for Advanced Glycation End products (RAGE) is involved in the pathogenesis of diabetes, and its complications. The aim of the present study is to examine the effect of RAGE ligand S100B on ABCA1 expression. METHODS S100B mediated regulation of LXR target genes like ABCA1, ABCG1, ABCG8, LXR-α and LXR-β in THP-1 cells was analyzed by real-time PCR, RT-PCR and western blots. ABCA1 mRNA expression in monocytes from diabetic patients was studied. Effect of LXR ligand on S100B induced changes in LXR target genes was also studied. Luciferase reporter assay was used for S100B induced ABCA1 promoter regulation. RESULTS S100B treatment resulted in a significant 2-3 fold reduction (p<0.01) in ABCA1 and ABCG1 mRNA in dose and time dependent manner in THP1 cells. ABCA1 protein level was also significantly (p<0.01) reduced. S100B-induced reduction on ABCA1 mRNA expression was blocked by treating THP-1 cell with anti-RAGE antibody. Reduced ABCA1 mRNA levels seen in peripheral blood monocytes from diabetes patients showed the in-vivo relevance of our in-vitro results. Effect of S100B on ABCA1 and ABCG1 expression was reversed by LXR ligand treatment. S100B treatment showed significant 2 fold (p<0.01) decrease in T1317 induced ABCA1 promoter activation. CONCLUSIONS These results show for the first time that ligation of RAGE with S100B can attenuate the expression of ABCA1 and ABCG1 through the LXRs. This could reduce ApoA-I-mediated cholesterol efflux from monocytes.
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Affiliation(s)
- Prabhakaran Kumar
- Diabetes and Cardiovascular Research Laboratory, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India
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Sorci G, Riuzzi F, Arcuri C, Tubaro C, Bianchi R, Giambanco I, Donato R. S100B protein in tissue development, repair and regeneration. World J Biol Chem 2013; 4:1-12. [PMID: 23580916 PMCID: PMC3622753 DOI: 10.4331/wjbc.v4.i1.1] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 03/01/2013] [Indexed: 02/05/2023] Open
Abstract
The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular regulatory activities. As an intracellular regulator, S100B is involved in the regulation of energy metabolism, transcription, protein phosphorylation, cell proliferation, survival, differentiation and motility, and Ca2+ homeostasis, by interacting with a wide array of proteins (i.e., enzymes, enzyme substrates, cytoskeletal subunits, scaffold/adaptor proteins, transcription factors, ubiquitin E3 ligases, ion channels) in a restricted number of cell types. As an extracellular signal, S100B engages the pattern recognition receptor, receptor for advanced glycation end-products (RAGE), on immune cells as well as on neuronal, astrocytic and microglial cells, vascular smooth muscle cells, skeletal myoblasts and cardiomyocytes. However, RAGE may not be the sole receptor activated by S100B, the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types. Moreover, extracellular effects of S100B vary depending on its local concentration. Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury, which is up to a few nM levels, S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis. The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development, repair and regeneration.
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Mohammadzadeh F, Desjardins JF, Tsoporis JN, Proteau G, Leong-Poi H, Parker TG. S100B: role in cardiac remodeling and function following myocardial infarction in diabetes. Life Sci 2012; 92:639-47. [PMID: 23000886 DOI: 10.1016/j.lfs.2012.09.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 08/27/2012] [Accepted: 09/07/2012] [Indexed: 01/16/2023]
Abstract
AIM S100B plays a role in cardiac remodeling following myocardial infarction (MI) and in diabetic vascular complications but not examined in diabetic myocardium. We thus examined the effects of targeted deletion of S100B gene on post-MI hearts. MAIN METHODS Coronary artery ligation or sham was performed 15 weeks after streptozotocin (STZ) or vehicle injection in wild-type (WT) and S100B knock-out (BKO) mice. Left ventricular (LV) structural and functional remodeling was studied 35 days after induction of MI. KEY FINDINGS In diabetes, post-MI remodeling exhibited an attenuated increase in LV mass, dilation, and myocyte hypertrophy in association with increased apoptosis and fibrosis and reduced matrix metalloproteinase-2 (MMP-2) activity. Despite reduced LV dilation, impairment of cardiac function was similar to non-diabetic controls. Both diabetes and MI alone induced myocardial S100B and its canonical receptor for advanced glycation end product (RAGE) expression. By contrast, in post-MI diabetic myocardium, S100B expression was attenuated. Diabetic BKO, following MI demonstrated increased ventricular dilation compared to WT, in association with greater impairment of cardiac function, GLUT4 expression and systemic AGE levels. SIGNIFICANCE These data suggest that S100B expression may serve to modulate cardiac metabolism and adverse consequences of AGE in diabetic post-MI remodeling and function.
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Affiliation(s)
- Forough Mohammadzadeh
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada
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Faa A, Senes G, Locci A, Pampaloni P, Pais ME, Piras B, d'Aloja E, Faa G. S100B protein expression in the heart of deceased individuals by overdose: a new forensic marker? Clinics (Sao Paulo) 2012; 67:821-6. [PMID: 22892929 PMCID: PMC3400175 DOI: 10.6061/clinics/2012(07)19] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 03/22/2012] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE The evaluation of S100B protein expression in the human heart and its correlation with drug-related death. METHOD Left ventricular samples were collected from 74 serial forensic autopsies (15 overdose-related deaths; 59 non-overdose-related deaths) from 2007 to 2010. Tissue sections from each sample were immunostained for S100B protein by a commercial antibody. RESULTS The S100B protein was detected in the heart samples of all 15 cases of drug-related deaths; S100B immunoreactivity was mainly observed in the cytoplasm of cardiomyocytes and as globular deposits in the interstitial spaces. No reactivity or weak reactivity was found in the cardiomyocytes of the 59 subjects who died of other causes. CONCLUSION Our preliminary data show that the S100B protein accumulates in injured cardiomyocytes during drug-related sudden death. Given the near absence of S100B protein in the heart of subjects who died from causes other than drug overdose, S100B immunopositivity may be used as a new ancillary screening tool for the postmortem diagnosis of overdose-related cardiac death.
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Affiliation(s)
- Armando Faa
- University of Cagliari, Department of Pathology, Cagliari, Italy.
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Hermann A, Donato R, Weiger TM, Chazin WJ. S100 calcium binding proteins and ion channels. Front Pharmacol 2012; 3:67. [PMID: 22539925 PMCID: PMC3336106 DOI: 10.3389/fphar.2012.00067] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 04/03/2012] [Indexed: 12/23/2022] Open
Abstract
S100 Ca(2+)-binding proteins have been associated with a multitude of intracellular Ca(2+)-dependent functions including regulation of the cell cycle, cell differentiation, cell motility and apoptosis, modulation of membrane-cytoskeletal interactions, transduction of intracellular Ca(2+) signals, and in mediating learning and memory. S100 proteins are fine tuned to read the intracellular free Ca(2+) concentration and affect protein phosphorylation, which makes them candidates to modulate certain ion channels and neuronal electrical behavior. Certain S100s are secreted from cells and are found in extracellular fluids where they exert unique extracellular functions. In addition to their neurotrophic activity, some S100 proteins modulate neuronal electrical discharge activity and appear to act directly on ion channels. The first reports regarding these effects suggested S100-mediated alterations in Ca(2+) fluxes, K(+) currents, and neuronal discharge activity. Recent reports revealed direct and indirect interactions with Ca(2+), K(+), Cl(-), and ligand activated channels. This review focuses on studies of the physical and functional interactions of S100 proteins and ion channels.
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Affiliation(s)
- Anton Hermann
- Division of Cellular and Molecular Neurobiology, Department of Cell Biology, University of SalzburgSalzburg, Austria
| | - Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, University of PerugiaPerugia, Italy
| | - Thomas M. Weiger
- Division of Cellular and Molecular Neurobiology, Department of Cell Biology, University of SalzburgSalzburg, Austria
| | - Walter J. Chazin
- Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt UniversityNashville, TN, USA
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Konecny F, Zou J, Husain M, von Harsdorf R. Post-myocardial infarct p27 fusion protein intravenous delivery averts adverse remodelling and improves heart function and survival in rodents. Cardiovasc Res 2012; 94:492-500. [PMID: 22492676 DOI: 10.1093/cvr/cvs138] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS P27Kip1 (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase 2 (cdk-2). Despite robust expression in the heart, little is known about the regulation and function of p27 in this terminally differentiated tissue. Previously, we demonstrated that p27 exerts anti-apoptotic and growth-inhibitory effects through interaction with casein kinase 2 (ck2) in neonatal rat cardiomyocytes. Here, we test the hypothesis that delivery of a transactivator of transcription (TAT)-p27 fusion protein (TAT.p27) will improve cardiac function and survival in a rat model of myocardial infarction (MI). METHODS AND RESULTS Fisher rats underwent permanent left anterior descending ligation-induced MI followed by iv injection of TAT.p27 or TAT.LacZ (20 mg/kg) on Days 1 and 7 post-MI. Delivery of TAT.p27 was evaluated by western blot (WB) and immunofluorescence microscopy. Heart function was assessed by echocardiography and pressure-volume catheter. Apoptosis, hypertrophy, and fibrosis were detected by histochemistry and morphometry. WB confirmed gradual reduction in endogenous cardiac p27 levels following MI, with immunohistochemistry demonstrating successful delivery of TAT.p27 to the heart. At 48 h post-MI, cardiac apoptosis was decreased in rats treated with TAT.p27 when compared with saline- and TAT.LacZ-treated controls. At 28 days post-MI, rats treated with TAT.p27 manifested less cardiomyocyte hypertrophy and fibrosis, less diminished cardiac function, and greater survival. Additionally, p27KO mice undergoing experimental MI suffered an early increase in apoptosis with a larger infarct size and markedly reduced survival when compared with wild-type (WT) controls. CONCLUSION These gain- and loss-of-function studies reveal a critical role for p27 in cardiac remodelling post-MI.
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Affiliation(s)
- Filip Konecny
- Toronto General Research Institute, 200 Elizabeth Street, MaRS 3-908, Toronto, ON, Canada M5G 2C4.
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Michetti F, Corvino V, Geloso MC, Lattanzi W, Bernardini C, Serpero L, Gazzolo D. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem 2012; 120:644-659. [PMID: 22145907 DOI: 10.1111/j.1471-4159.2011.07612.x] [Citation(s) in RCA: 173] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
S100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target.
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Affiliation(s)
- Fabrizio Michetti
- Institute of Anatomy and Cell Biology, Università Cattolica Sacro Cuore, Roma, Italy.
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BRCA1 is an essential regulator of heart function and survival following myocardial infarction. Nat Commun 2011; 2:593. [PMID: 22186889 PMCID: PMC3247816 DOI: 10.1038/ncomms1601] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 11/16/2011] [Indexed: 12/30/2022] Open
Abstract
The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure. The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer. Now, Shukla et al. demonstrate that mice lacking BRCA1 in cardiomyocytes are more sensitive to ischaemia than control mice, and that BRCA1 is elevated in human tissues exposed to ischaemia, suggesting a cardioprotective role for BRCA1.
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Dessing MC, Pulskens WP, Teske GJ, Butter LM, van der Poll T, Yang H, Tracey KJ, Nawroth PP, Bierhaus A, Florquin S, Leemans JC. RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury. J Innate Immun 2011; 4:80-5. [PMID: 22067944 DOI: 10.1159/000334251] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 10/10/2011] [Indexed: 01/03/2023] Open
Abstract
The receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses in renal diseases, but its role in renal ischemia/reperfusion (I/R) injury is unknown. We showed that during renal I/R, RAGE ligands HMGB1 and S100B are expressed. However, RAGE deficiency does not affect renal injury and function upon I/R-induced injury.
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Affiliation(s)
- Mark C Dessing
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Tsoporis JN, Izhar S, Proteau G, Slaughter G, Parker TG. S100B-RAGE dependent VEGF secretion by cardiac myocytes induces myofibroblast proliferation. J Mol Cell Cardiol 2011; 52:464-73. [PMID: 21889514 DOI: 10.1016/j.yjmcc.2011.08.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 08/09/2011] [Accepted: 08/16/2011] [Indexed: 12/30/2022]
Abstract
Post-infarct remodeling is associated with the upregulation of the receptor for advanced glycation end products (RAGE), the induction of its ligand the calcium binding protein S100B and the release of the potent endothelial-cell specific mitogen vascular endothelial growth factor (VEGF). To determine a possible functional interaction between S100B, RAGE and VEGF we stimulated rat neonatal cardiac myocyte cultures transfected with either RAGE or a dominant-negative cytoplasmic deletion mutant of RAGE with S100B for 48 h. Under baseline conditions, cardiac myocytes express low levels of RAGE and VEGF and secrete VEGF in the medium as measured by ELISA. In RAGE overexpressing myocytes, S100B (100 nM) resulted in increases in VEGF mRNA, VEGF protein, VEGF secretion, and activation of the transcription factor NF-κB. Pre-treatment of RAGE overexpressing myocytes with the NF-κB inhibitor caffeic acid phenethyl ester inhibited increases in VEGF mRNA, VEGF protein and VEGF in the medium by S100B. In myocytes expressing dominant-negative RAGE, S100B did not induce VEGF mRNA, VEGF protein, VEGF secretion or NF-κB activation. In culture, rat neonatal and adult cardiac fibroblasts undergo phenotypic transition to myofibroblasts. Treatment of neonatal and adult myofibroblasts with VEGF (10 ng/mL) induces VEGFR-2 (flk-1/KDR) tyrosine kinase phosphorylation, ERK1/2 phosphorylation and myofibroblast proliferation. Together these data demonstrate that secreted VEGF by cardiac myocytes in response to S100B via RAGE ligation induces myofibroblast proliferation potentially contributing to scar formation observed in infarcted myocardium. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
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Affiliation(s)
- James N Tsoporis
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
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Cai XY, Lu L, Wang YN, Jin C, Zhang RY, Zhang Q, Chen QJ, Shen WF. Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia-reperfusion injury. Atherosclerosis 2011; 217:536-42. [PMID: 21663912 DOI: 10.1016/j.atherosclerosis.2011.05.023] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Revised: 05/18/2011] [Accepted: 05/19/2011] [Indexed: 10/18/2022]
Abstract
OBJECTIVE We aim to check if serum levels of receptor for advanced glycation endproduct (RAGE) ligands S100B, S100A6 and S100P were related to myocardial injury in acute coronary syndrome (ACS). METHODS Serum levels of S100B, S100A6, S100P, and soluble RAGE (sRAGE) were analyzed in 882 patients. Based upon clinical and laboratory findings, they were assigned into control (n=251), stable angina (n=211), and ACS (n=420). To verify clinical data of ACS, forty Sprague-Dawley rats were subjected to cardiac ischemia-reperfusion (I/R) injury by occluding proximal (large infarct size; n=20) or distal (small infarct size; n=20) left anterior descending coronary artery, and another 20 rats were in sham-operation group. The expressions of S100B, S100A6, S100P and RAGE in the myocardium were analyzed. RESULTS Serum levels of S100B, S100A6 and S100P were higher in ACS group than in stable angina and control groups, and sRAGE levels were higher in ACS patients versus controls (all p<0.01). S100B and S100P levels correlated significantly with CK-MB and troponin I levels in ACS group (all p<0.05). In multivariable regression analysis, S100B, S100A6, S100P and conventional risk factors were independently associated with ACS. In animal models, the expressions of S100B, S100A6 and S100P were closely related to infarct size (all p<0.05). CONCLUSION This study indicates that serum levels of S100B, S100A6 and S100P are associated with ACS, and serum levels and myocardial expression of these proteins are related to infarct size.
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Affiliation(s)
- Xue Ying Cai
- Department of Cardiology, Rui Jin Hospital, Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China
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Li JP, Lu L, Wang LJ, Zhang FR, Shen WF. Increased serum levels of S100B are related to the severity of cardiac dysfunction, renal insufficiency and major cardiac events in patients with chronic heart failure. Clin Biochem 2011; 44:984-8. [PMID: 21640093 DOI: 10.1016/j.clinbiochem.2011.05.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 04/08/2011] [Accepted: 05/13/2011] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To investigate the correlations between S100B and the severity of cardiac dysfunction, renal insufficiency (RI) and prognosis in chronic heart failure (CHF). METHOD Serum levels of S100B, TNF-α, high sensitivity CRP and NT-proBNP were determined in CHF patients with (n=96) and without RI (n=146). Patients with RI only (n=62) and control subjects (n=64) served for comparison. Patients were followed up for one year. RESULTS S100B levels were higher in CHF patients with a further elevation in those with RI (P<0.01). Serum S100B levels correlated with left ventricular ejection fraction, left ventricular end-diastolic volume and NT-proBNP in CHF patients, and eGFR in patients with RI (all P<0.05). Increased S100B levels were associated with major cardiac events (MCE), and were independently associated with the presence of CHF (all P<0.05). CONCLUSION Increased serum S100B levels were associated with the severity of cardiac dysfunction, RI and an adverse prognosis in CHF patients. It represents an independent risk factor for CHF.
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Affiliation(s)
- Jin Ping Li
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, PR China
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40
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The significance of protein S-100B testing in cardiac arrest patients. Clin Biochem 2011; 44:567-75. [PMID: 21458434 DOI: 10.1016/j.clinbiochem.2011.03.133] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Accepted: 03/20/2011] [Indexed: 11/24/2022]
Abstract
Cardiac arrest often represents the first expression of an underlying cardiac disease. Despite advances in neurocritical care, the neurological assessment of cardiac arrest patients relies on clinical, instrumental and biochemical parameters. The clinical significance of S-100 calcium binding protein B (S-100B) has substantially increased throughout several areas of clinical neuroscience, but reliable evidences attest it can be used as a reliable and early predictor of poor physiological and cognitive neurological outcomes after cardiac arrest.
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Pol CJ, Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A, Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS. Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 2011; 152:669-79. [PMID: 21159857 DOI: 10.1210/en.2010-0431] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice. Pathological remodeling of the noninfarcted part of the LV was evident from cardiomyocyte hypertrophy, interstitial fibrosis, and impairment of contractility. These changes were maximal and stable from the first week onward, as was the degree of LV dilation. A strong induction of D3 activity was found, which was similarly stable for the period examined. Plasma T(4) levels were transiently decreased at 1 wk after MI, but T(3) levels remained normal. The high D3 activity was associated with increased D3 mRNA expression at 1 but not at 4 and 8 wk after MI. Immunohistochemistry localized D3 protein to cardiomyocytes. In vivo measurement of TH-dependent transcription activity in cardiomyocytes using a luciferase reporter assay indicated a 48% decrease in post-MI mice relative to sham-operated animals, and this was associated with a 50% decrease in LV tissue T(3) concentration. In conclusion, pathological ventricular remodeling after MI in the mouse leads to high and stable induction of D3 activity in cardiomyocytes and a local hypothyroid condition.
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Affiliation(s)
- Christine J Pol
- Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, 1081 HV Amsterdam, The Netherlands
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Effects of S100B on Serotonergic Plasticity and Neuroinflammation in the Hippocampus in Down Syndrome and Alzheimer's Disease: Studies in an S100B Overexpressing Mouse Model. Cardiovasc Psychiatry Neurol 2010; 2010. [PMID: 20827311 PMCID: PMC2933893 DOI: 10.1155/2010/153657] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 06/01/2010] [Accepted: 07/02/2010] [Indexed: 12/17/2022] Open
Abstract
S100B promotes development and maturation in the mammalian brain. However, prolonged or extensive exposure can lead to neurodegeneration. Two important functions of S100B in this regard, are its role in the development and plasticity of the serotonergic neurotransmitter system, and its role in the cascade of glial changes associated with neuroinflammation. Both of these processes are therefore accelerated towards degeneration in disease processes wherein S100B is increased, notably, Alzheimer's disease (AD) and Down syndrome (DS).
In order to study the role of S100B in this context, we have examined S100B overexpressing transgenic mice. Similar to AD and DS, the transgenic animals show a profound change in serotonin innervation. By 28 weeks of age, there is a significant loss of terminals in the hippocampus. Similarly, the transgenic animals show neuroinflammatory changes analogous with AD and DS. These include decreased numbers of mature, stable astroglial cells, increased numbers of activated microglial cells and increased microglial expression of the cell surface receptor RAGE. Eventually, the S100B transgenic animals show neurodegeneration and the appearance of hyperphosphorylated tau structures, as seen in late stage DS and AD. The role of S100B in these conditions is discussed.
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Sorci G, Bianchi R, Riuzzi F, Tubaro C, Arcuri C, Giambanco I, Donato R. S100B Protein, A Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond. Cardiovasc Psychiatry Neurol 2010; 2010:656481. [PMID: 20827421 PMCID: PMC2933911 DOI: 10.1155/2010/656481] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 06/08/2010] [Indexed: 12/15/2022] Open
Abstract
S100B belongs to a multigenic family of Ca(2+)-binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), Ca(2+) homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation.
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Affiliation(s)
- Guglielmo Sorci
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Roberta Bianchi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Francesca Riuzzi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Claudia Tubaro
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Cataldo Arcuri
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
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Rohde D, Ritterhoff J, Voelkers M, Katus HA, Parker TG, Most P. S100A1: a multifaceted therapeutic target in cardiovascular disease. J Cardiovasc Transl Res 2010; 3:525-37. [PMID: 20645037 PMCID: PMC2933808 DOI: 10.1007/s12265-010-9211-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 07/02/2010] [Indexed: 01/02/2023]
Abstract
Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca(2+) binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca(2+) handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists.
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Affiliation(s)
- David Rohde
- Laboratory for Molecular and Translational Cardiology, Division of Cardiology, Department of Internal Medicine III, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
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Intracellular and Extracellular Effects of S100B in the Cardiovascular Response to Disease. Cardiovasc Psychiatry Neurol 2010; 2010:206073. [PMID: 20672023 PMCID: PMC2909713 DOI: 10.1155/2010/206073] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Accepted: 05/06/2010] [Indexed: 01/11/2023] Open
Abstract
S100B, a calcium-binding protein of the EF-hand type, exerts both intracellular and extracellular functions. S100B is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced expression of S100B in neonatal rat myocyte cultures and high level expression of S100B in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype but augments myocyte apoptosis following myocardial infarction. By contrast, knocking out S100B, augments hypertrophy, decreases apoptosis and preserves cardiac function following myocardial infarction. Expression of S100B in aortic smooth muscle cells inhibits cell proliferation and the vascular response to adrenergic stimulation. S100B induces apoptosis by an extracellular mechanism via interaction with the receptor for advanced glycation end products and activating ERK1/2 and p53 signaling. The intracellular and extracellular roles of S100B are attractive therapeutic targets for the treatment of both cardiac and vascular diseases.
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Zhou SY, Mamdani M, Qanud K, Shen JB, Pappano AJ, Kumar TS, Jacobson KA, Hintze T, Recchia FA, Liang BT. Treatment of heart failure by a methanocarba derivative of adenosine monophosphate: implication for a role of cardiac purinergic P2X receptors. J Pharmacol Exp Ther 2010; 333:920-8. [PMID: 20200116 PMCID: PMC2879931 DOI: 10.1124/jpet.109.164376] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 02/25/2010] [Indexed: 01/24/2023] Open
Abstract
Evidence is accumulating to support a potentially important role for purinergic (P2X) receptors in heart failure (HF). We tested the hypothesis that a hydrolysis-resistant nucleotide analog with agonist activity at myocardial P2X receptors (P2XRs) improves the systolic HF phenotype in mouse and dog models. We developed a hydrolysis-resistant adenosine monophosphate derivative, (1'S,2R,3S,4'R,5'S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.1.0]hexane-2,3-diol) (MRS2339), with agonist activity at native cardiac P2XRs. Chronic MRS2339 infusion in postinfarct and calsequestrin (CSQ) mice with HF resulted in higher rates of pressure change (+dP/dt), left ventricle (LV)-developed pressure, and cardiac output in an in vitro working heart model. Heart function in vivo, as determined by echocardiography-derived fractional shortening, was also improved in MRS2339-infused mice. The beneficial effect of MRS2339 was dose-dependent and was identical to that produced by cardiac myocyte-specific overexpression of the P2X(4) receptor. The HF improvement was associated with the preservation of LV wall thickness in both systole and diastole in postinfarct and CSQ mice. In dogs with pacing-induced HF, MRS2339 infusion reduced left ventricular end-diastolic pressure, improved arterial oxygenation, and increased +dP/dt. MRS2339 treatment also decreased LV chamber size in mice and dogs with HF. In murine and canine models of systolic HF, in vivo administration of a P2X nucleotide agonist improved contractile function and cardiac performance. These actions were associated with preserved LV wall thickness and decreased LV remodeling. The data are consistent with a role of cardiac P2XRs in mediating the beneficial effect of this agonist.
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Affiliation(s)
- Si-Yuan Zhou
- The Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
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Kumar TS, Zhou SY, Joshi BV, Balasubramanian R, Yang T, Liang BT, Jacobson KA. Structure-activity relationship of (N)-Methanocarba phosphonate analogues of 5'-AMP as cardioprotective agents acting through a cardiac P2X receptor. J Med Chem 2010; 53:2562-76. [PMID: 20192270 PMCID: PMC2880888 DOI: 10.1021/jm9018542] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH(3)-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.
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Affiliation(s)
- T. Santhosh Kumar
- Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Si-Yuan Zhou
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06030
| | - Bhalchandra V. Joshi
- Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Ramachandran Balasubramanian
- Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Tiehong Yang
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06030
| | - Bruce T. Liang
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06030
| | - Kenneth A. Jacobson
- Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
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Abstract
The immunoglobulin superfamily molecule RAGE (receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), advanced oxidation protein products, S100/calgranulins, high-mobility group box-1, amyloid-beta peptide, and beta-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart. Together with increased expression of RAGE in diabetic settings, we propose that release and accumulation of RAGE ligands contribute to exaggerated cellular damage. Stopping the vicious cycle of AGE-RAGE and RAGE axis signaling in the vulnerable heart and great vessels may be essential in controlling and preventing the consequences of diabetes.
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Affiliation(s)
- Shi Fang Yan
- Division of Surgical Science, Department of Surgery, Columbia University, 630 W 168th St, P&S 17-401, New York, NY 10032, USA
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Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: a physiological and gene expression-based approach. Crit Care Med 2010; 38:894-902. [PMID: 20101178 DOI: 10.1097/ccm.0b013e3181ce4e50] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Increased nitric oxide production and altered mitochondrial function have been implicated in sepsis-induced cardiac dysfunction. The molecular mechanisms underlying myocardial depression in sepsis and the contribution of nitric oxide in this process however, are incompletely understood. OBJECTIVES To assess the transcriptional profile associated with sepsis-induced myocardial depression in a clinically relevant mouse model, and specifically test the hypothesis that critical transcriptional changes are inducible nitric oxide synthase-dependent. DESIGN Laboratory investigation. SETTING University affiliated research laboratory. SUBJECTS C57/BL6 wild type and congenic B6 129P2-Nos2tm1Lau/J (iNOS) mice. INTERVENTIONS Assessment of myocardial function after 48 hrs of induction of polymicrobial sepsis by caecal ligation and perforation. MEASUREMENTS AND RESULTS We compared the myocardial transcriptional profile in C57/BL6 wild type mice and congenic B6 129P2-Nos2tm1Lau/J litter mates after 48 hrs of polymicrobial sepsis induced by caecal ligation and perforation. Profiling of 22,690 expressed sequence tags by gene set enrichment analysis demonstrated that inducible nitric oxide synthase -/- failed to down regulate critical bioenergy and metabolism related genes including the gene for peroxisome proliferator-activated receptor gamma coactivator 1. Bioinformatics analysis identified a striking concordance in down regulation of transcriptional activity of proliferator-activated receptor gamma coactivator 1-related transcription factors resulting in sepsis associated myocardial remodeling as shown by isoform switching in the expression of contractile protein myosin heavy chain. In inducible nitric oxide synthase -/- deficient mice, contractile depression was minimal, and the transcriptional switch was absent. CONCLUSIONS Metabolic and myosin isoform gene expression switch in sepsis-induced myocardial depression is inducible nitric oxide synthase-dependent. Furthermore, we suggest that the molecular switch favoring the expression of fetal isoforms of contraction related proteins is associated with regulation of proliferator-activated receptor gamma coactivator 1 and related transcription factors in an inducible nitric oxide synthase-dependent manner.
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S100B: a multifunctional role in cardiovascular pathophysiology. Amino Acids 2010; 41:843-7. [PMID: 20204434 DOI: 10.1007/s00726-010-0527-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 02/11/2010] [Indexed: 01/16/2023]
Abstract
S100B, a calcium-binding protein of the EF-hand type exerts both intracellular and extracellular functions. S100B is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced expression of S100B in neonatal rat myocyte cultures, and high level expression of S100B in transgenic mice hearts and aortic smooth muscle cells inhibit cardiac hypertrophy and the associated phenotype, arterial smooth muscle proliferation, respectively, but demonstrate increased apoptosis following α(1)-adrenergic stimulation or myocardial infarction. Knocking out S100B, augmented hypertrophy, decreased apoptosis and preserved cardiac function following myocardial infarction. S100B induces apoptosis by an extracellular mechanism by interacting with the receptor for advanced glycation end products and activating ERK1/2 and p53 signaling. The intracellular, and extracellular, roles of S100B are attractive therapeutic targets for the treatment of both cardiac and vascular disease.
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