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Krukowski DC, Rao VN. Exposing Faults in the Foundation: Sodium-restrictive Guidance for Ambulatory Heart Failure. J Card Fail 2024; 30:1083-1085. [PMID: 39068983 DOI: 10.1016/j.cardfail.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 07/19/2024] [Indexed: 07/30/2024]
Affiliation(s)
- Danielle C Krukowski
- Division of Cardiovascular Medicine, Medical University of South Carolina, Charleston, SC
| | - Vishal N Rao
- Division of Cardiovascular Medicine, Medical University of South Carolina, Charleston, SC; The Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC.
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2
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Dhalla NS, Bhullar SK, Adameova A, Mota KO, de Vasconcelos CML. Status of β 1-Adrenoceptor Signal Transduction System in Cardiac Hypertrophy and Heart Failure. Rev Cardiovasc Med 2023; 24:264. [PMID: 39076390 PMCID: PMC11270071 DOI: 10.31083/j.rcm2409264] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 07/31/2024] Open
Abstract
Although β 1-adrenoceptor ( β 1-AR) signal transduction, which maintains cardiac function, is downregulated in failing hearts, the mechanisms for such a defect in heart failure are not fully understood. Since cardiac hypertrophy is invariably associated with heart failure, it is possible that the loss of β 1-AR mechanisms in failing heart occurs due to hypertrophic process. In this regard, we have reviewed the information from a rat model of adaptive cardiac hypertrophy and maladaptive hypertrophy at 4 and 24 weeks after inducing pressure overload as well as adaptive cardiac hypertrophy and heart failure at 4 and 24 weeks after inducing volume overload, respectively. Varying degrees of alterations in β 1-AR density as well as isoproterenol-induced increases in cardiac function, intracellular Ca 2 + -concentration in cardiomyocytes and adenylyl cyclase activity in crude membranes have been reported under these hypertrophic conditions. Adaptive hypertrophy at 4 weeks of pressure or volume overload showed unaltered or augmented increases in the activities of different components of β 1-AR signaling. On the other hand, maladaptive hypertrophy due to pressure overload and heart failure due to volume overload at 24 weeks revealed depressions in the activities of β 1-AR signal transduction pathway. These observations provide evidence that β 1-AR signal system is either unaltered or upregulated in adaptive cardiac hypertrophy and downregulated in maladaptive cardiac hypertrophy or heart failure. Furthermore, the information presented in this article supports the concept that downregulation of β 1-AR mechanisms in heart failure or maladaptive cardiac hypertrophy is not due to hypertrophic process per se. It is suggested that a complex mechanism involving the autonomic imbalance may be of a critical importance in determining differential alterations in non-failing and failing hearts.
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Affiliation(s)
- Naranjan S. Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, and Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
| | - Sukhwinder K. Bhullar
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, and Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
| | - Adriana Adameova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University and Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 811 03 Bratislava, Slovakia
| | - Karina Oliveira Mota
- Heart Biophysics Laboratory, Department of Physiology, Center for Biological and Health Sciences, Federal University of Sergipe, 73330 Sergipe, Brazil
| | - Carla Maria Lins de Vasconcelos
- Heart Biophysics Laboratory, Department of Physiology, Center for Biological and Health Sciences, Federal University of Sergipe, 73330 Sergipe, Brazil
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3
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Farooq MA, Ajmal I, Hui X, Chen Y, Ren Y, Jiang W. β2-Adrenergic Receptor Mediated Inhibition of T Cell Function and Its Implications for CAR-T Cell Therapy. Int J Mol Sci 2023; 24:12837. [PMID: 37629018 PMCID: PMC10454818 DOI: 10.3390/ijms241612837] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/05/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu.
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Affiliation(s)
| | | | | | | | | | - Wenzheng Jiang
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; (M.A.F.); (I.A.)
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Zheng H, Peri L, Ward GK, Sanders KM, Ward SM. Cardiac PDGFRα + interstitial cells generate spontaneous inward currents that contribute to excitability in the heart. FASEB J 2023; 37:e22929. [PMID: 37086093 PMCID: PMC10402933 DOI: 10.1096/fj.202201712r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/06/2023] [Accepted: 04/05/2023] [Indexed: 04/23/2023]
Abstract
The cell types and conductance that contribute to normal cardiac functions remain under investigation. We used mice that express an enhanced green fluorescent protein (eGFP)-histone 2B fusion protein driven off the cell-specific endogenous promoter for Pdgfra to investigate the distribution and functional role of PDGFRα+ cells in the heart. Cardiac PDGFRα+ cells were widely distributed within the endomysium of atria, ventricle, and sino-atrial node (SAN) tissues. PDGFRα+ cells formed a discrete network of cells, lying in close apposition to neighboring cardiac myocytes in mouse and Cynomolgus monkey (Macaca fascicularis) hearts. Expression of eGFP in nuclei allowed unequivocal identification of these cells following enzymatic dispersion of muscle tissues. FACS purification of PDGFRα+ cells from the SAN and analysis of gene transcripts by qPCR revealed that they were a distinct population of cells that expressed gap junction transcripts, Gja1 and Gjc1. Cardiac PDGFRα+ cells generated spontaneous transient inward currents (STICs) and spontaneous transient depolarizations (STDs) that reversed at 0 mV. Reversal potential was maintained when ECl = -40 mV. [Na+ ]o replacement and FTY720 abolished STICs, suggesting they were due to a non-selective cation conductance (NSCC) carried by TRPM7. PDGFRα+ cells also express β2 -adrenoceptor gene transcripts, Adrb2. Zinterol, a selective β2 -receptor agonist, increased the amplitude and frequency of STICs, suggesting these cells could contribute to adrenergic regulation of cardiac excitability. PDGFRα+ cells in cardiac muscles generate inward currents via an NSCC. STICs generated by these cells may contribute to the integrated membrane potentials of cardiac muscles, possibly affecting the frequency of pacemaker activity.
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Affiliation(s)
- Haifeng Zheng
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA
| | - Lauren Peri
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA
| | - Grace K. Ward
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA
| | - Kenton M. Sanders
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA
| | - Sean M. Ward
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA
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Fernandez CJ, Hanna FW, Pacak K, Nazari MA. Catecholamines and blood pressure regulation. ENDOCRINE HYPERTENSION 2023:19-34. [DOI: 10.1016/b978-0-323-96120-2.00010-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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6
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Arcoraci V, Squadrito F, Rottura M, Barbieri MA, Pallio G, Irrera N, Nobili A, Natoli G, Argano C, Squadrito G, Corrao S. Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register. Front Cardiovasc Med 2022; 9:876693. [PMID: 35651906 PMCID: PMC9149000 DOI: 10.3389/fcvm.2022.876693] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/05/2022] [Indexed: 11/30/2022] Open
Abstract
Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations.
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Affiliation(s)
- Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
- SunNutraPharma, Academic Spin-Off Company of the University of Messina, Messina, Italy
| | - Michelangelo Rottura
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | | | - Giovanni Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Alessandro Nobili
- Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Giuseppe Natoli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, PROMISE, University of Palermo, Palermo, Italy
| | - Christiano Argano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, PROMISE, University of Palermo, Palermo, Italy
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Salvatore Corrao
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, PROMISE, University of Palermo, Palermo, Italy
- Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Palermo, Italy
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7
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Sharma A, Ahmad S, Ahmad T, Ali S, Syed MA. Mitochondrial dynamics and mitophagy in lung disorders. Life Sci 2021; 284:119876. [PMID: 34389405 DOI: 10.1016/j.lfs.2021.119876] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022]
Abstract
Mitochondria are biosynthetic, bioenergetic, and signaling organelles which are critical for physiological adaptations and cellular stress responses to the environment. Various endogenous and environmental stress affects critical processes in mitochondrial homeostasis such as oxidative phosphorylation, biogenesis, mitochondrial redox system which leads to the formation of reactive oxygen species (ROS) and free radicals. The state of function of the mitochondrion is particularly dependent on the dynamic balance between mitochondrial biogenesis, fusion and fission, and degradation of damaged mitochondria by mitophagy. Increasing evidence has suggested a prominent role of mitochondrial dysfunction in the onset and progression of various lung pathologies, ranging from acute to chronic disorders. In this comprehensive review, we discuss the emerging findings of multifaceted regulations of mitochondrial dynamics and mitophagy in normal lung homeostasis as well as the prominence of mitochondrial dysfunction as a determining factor in different lung disorders such as lung cancer, COPD, IPF, ALI/ARDS, BPD, and asthma. The review will contribute to the existing understanding of critical molecular machinery regulating mitochondrial dynamic state during these pathological states. Furthermore, we have also highlighted various molecular checkpoints involved in mitochondrial dynamics, which may serve as hopeful therapeutic targets for the development of potential therapies for these lung disorders.
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Affiliation(s)
- Archana Sharma
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Shaniya Ahmad
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Tanveer Ahmad
- Multidisciplinary Centre for Advance Research and Studies, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Shakir Ali
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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Malhotra V, Vats M, Nath R, Mehta S, Kumar R, Bhalla M, Sinha JN, Shanker K, Pathak SR. Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents. Bioorg Med Chem Lett 2020; 30:127595. [PMID: 33031924 DOI: 10.1016/j.bmcl.2020.127595] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/24/2020] [Accepted: 09/26/2020] [Indexed: 01/06/2023]
Abstract
A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).
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Affiliation(s)
- Vineet Malhotra
- Department of Pharmacology & Therapeutics, KGMU, Lucknow, India
| | - Monika Vats
- Department of Chemistry, Biochemistry & Forensic Science, Amity School of Applied Sciences, Amity University Haryana, Gurugram 122413, India
| | - Rajendra Nath
- Department of Pharmacology & Therapeutics, KGMU, Lucknow, India
| | - Simpi Mehta
- Department of Chemistry, Biochemistry & Forensic Science, Amity School of Applied Sciences, Amity University Haryana, Gurugram 122413, India
| | - Rakesh Kumar
- Department of Chemistry, Biochemistry & Forensic Science, Amity School of Applied Sciences, Amity University Haryana, Gurugram 122413, India
| | - Manish Bhalla
- Department of Pharmacology & Therapeutics, KGMU, Lucknow, India
| | - J N Sinha
- Department of Pharmacology & Therapeutics, KGMU, Lucknow, India
| | - K Shanker
- Department of Pharmacology & Therapeutics, KGMU, Lucknow, India
| | - Seeema R Pathak
- Department of Chemistry, Biochemistry & Forensic Science, Amity School of Applied Sciences, Amity University Haryana, Gurugram 122413, India.
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Alam MJ, Gupta R, Mahapatra NR, Goswami SK. Catestatin reverses the hypertrophic effects of norepinephrine in H9c2 cardiac myoblasts by modulating the adrenergic signaling. Mol Cell Biochem 2019; 464:205-219. [PMID: 31792650 DOI: 10.1007/s11010-019-03661-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypothesized that CST moderates the adrenergic overdrive and studied its effects on norepinephrine-mediated hypertrophic responses in H9c2 cardiac myoblasts. CST alone regulated the expression of a number of fetal genes that are induced during hypertrophy. When cells were pre-treated CST, it blunted the modulation of those genes by norepinephrine. Norepinephrine (2 µM) treatment also increased cell size and enhanced the level of Troponin T in the sarcomere. These effects were attenuated by the treatment with CST. CST attenuated the immediate generation of ROS and the increase in glutathione peroxidase activity induced by norepinephrine treatment. Expression of fosB and AP-1 promoter-reporter constructs was used as the endpoint readout for the interaction between the CST and adrenergic signals at the gene level. It showed that CST largely attenuates the stimulatory effects of norepinephrine and other mitogenic signals through the modulation of the gene regulatory modules in a characteristic manner. Depending upon the dose, the signaling by CST appears to be disparate, and at 10-25 nM doses, it primarily moderated the signaling by the β1/2-adrenoceptors. This study, for the first time, provides insights into the modulation of adrenergic signaling in the heart by CST.
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Affiliation(s)
- Md Jahangir Alam
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Fridabad, 121001, India
| | - Richa Gupta
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Shyamal K Goswami
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Fridabad, 121001, India.
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Sessa M, Mascolo A, Rasmussen DB, Kragholm K, Jensen MT, Sportiello L, Rafaniello C, Tari GM, Pagliaro C, Andersen M, Rossi F, Capuano A. Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study. Sci Rep 2019; 9:11465. [PMID: 31391573 PMCID: PMC6685956 DOI: 10.1038/s41598-019-47967-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/27/2019] [Indexed: 12/13/2022] Open
Abstract
Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases (Italy) were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio, OR 8.20; 95% Confidence Interval, 95% CI 1.30–51.80), cerebrovascular thrombosis (OR 7.06; 95% CI 1.14–43.68), chronic kidney disease (OR 4.32; 95% CI 1.16–16.02), and acute heart failure (OR 1.97; 95% CI 1.28–3.03) hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin (OR 3.00; 95% CI 1.24–7.24), fondaparinux (OR 2.47; 95% CI 1.17–5.21) or strontium ranelate (OR 2.03; 95% CI 1.06–3.90) redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.
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Affiliation(s)
- Maurizio Sessa
- Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, København Ø, Denmark. .,Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy.
| | - Annamaria Mascolo
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
| | - Daniel Bech Rasmussen
- Respiratory Research Unit Zealand, Department of Respiratory Medicine, Naestved Hospital, Ringstedgade 61, 4700, Næstved, Denmark.,Department of Cardiology, Herlev and Gentofte University Hospital, Gentofte Hospitalsvej 1, 2900, Hellerup, Denmark
| | - Kristian Kragholm
- Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Hobrovej 18-22, 9100, Aalborg, Denmark
| | - Magnus Thorsten Jensen
- Heart Centre, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100, København, Denmark
| | - Liberata Sportiello
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
| | - Concetta Rafaniello
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
| | | | - Claudia Pagliaro
- Caserta Local Health Unit, Via Unità Italiana 28, 81100, Caserta, Italy
| | - Morten Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, København Ø, Denmark
| | - Francesco Rossi
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
| | - Annalisa Capuano
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
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11
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Val-Blasco A, Navarro-García JA, Tamayo M, Piedras MJ, Prieto P, Delgado C, Ruiz-Hurtado G, Rozas-Romero L, Gil-Fernández M, Zaragoza C, Boscá L, Fernández-Velasco M. Deficiency of NOD1 Improves the β-Adrenergic Modulation of Ca 2+ Handling in a Mouse Model of Heart Failure. Front Physiol 2018; 9:702. [PMID: 29962957 PMCID: PMC6010671 DOI: 10.3389/fphys.2018.00702] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/22/2018] [Indexed: 02/05/2023] Open
Abstract
Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during β-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the β-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of β1 and β2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under β-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the β-adrenergic modulation of Ca2+ handling in failing hearts.
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Affiliation(s)
- Almudena Val-Blasco
- Innate Immune Response Group, Instituto de Investigación Hospital Universitario La Paz, La Paz University Hospital, Madrid, Spain
| | - Jose A. Navarro-García
- Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Maria Tamayo
- Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Maria J. Piedras
- Department of Anatomy, Faculty of Health Sciences, Francisco de Vitoria University (UFV), Pozuelo de Alarcón, Spain
| | - Patricia Prieto
- Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Carmen Delgado
- Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Gema Ruiz-Hurtado
- Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Laura Rozas-Romero
- Innate Immune Response Group, Instituto de Investigación Hospital Universitario La Paz, La Paz University Hospital, Madrid, Spain
| | - Marta Gil-Fernández
- Innate Immune Response Group, Instituto de Investigación Hospital Universitario La Paz, La Paz University Hospital, Madrid, Spain
| | - Carlos Zaragoza
- Unidad de Investigación Cardiovascular, Universidad Francisco de Vitoria, Hospital Universitario Ramón y Cajal (IRYCIS), CIBERCV, Madrid, Spain
| | - Lisardo Boscá
- Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - María Fernández-Velasco
- Innate Immune Response Group, Instituto de Investigación Hospital Universitario La Paz, La Paz University Hospital, Madrid, Spain
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Non-cardiac Surgery After Heart Transplantation. Anesthesiology 2017. [DOI: 10.1007/978-3-319-50141-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Sestini S, Pestelli F, Leoncini M, Bellandi F, Mazzeo C, Mansi L, Carrio I, Castagnoli A. The natural history of takotsubo syndrome: a two-year follow-up study with myocardial sympathetic and perfusion G-SPECT imaging. Eur J Nucl Med Mol Imaging 2016; 44:267-283. [PMID: 27909770 DOI: 10.1007/s00259-016-3575-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/18/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE To investigate changes in sympathetic activity, perfusion, and left ventricular (LV) functionality in takotsubo cardiomyopathy (TTC) patients from onset (T0) to post-onset conditions at 1 month (T1), 1-2 years (T2, T3). METHODS Twenty-two patients (70 ± 11 years) underwent serial gated single photon emission tomography (G-SPECT) studies with 123I-mIBG and 99mTc-Sestamibi. Statistics were performed using ANOVA/Sheffé post-hoc, correlation test, and receiver operating characteristic (ROC) curve analysis (p < 0.05). RESULTS Patients presented at T0 with LV ballooning and reduced early-late mIBG uptake (95%, 100%), left ventricular ejection fraction (LVEF)G-SPECT (86%) and perfusion (77 %). Adrenergic dysfunction was greater in apex, it overlaps with contractile impairment, and both were more severe than perfusion defect. During follow-up, LVEFG-SPECT, contractility, and perfusion were normal, while 82% and 90% of patients at T1 and 50% at T2 and T3 continued to show a reduced apical early-late mIBG distribution. These patients presented at T0-T1 with greater impairment of adrenergic function, contractility, and perfusion. A relationship was present within innervation and both perfusion and contractile parameters at T0 and T1, and between the extent of adrenergic defect at T3 and both the defect extent and age at T0 (cut-off point 42.5%, 72 years). CONCLUSION Outcome for TTC is not limited to a reversible contractile and perfusion abnormalities, but it includes residual adrenergic dysfunction, depending on the level of adrenergic impairment and age of patients at onset. The number of patients, as well as degree of perfusion abnormalities were found to be higher than those previously reported possibly depending on the time-interval between hospital admission and perfusion scan.
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Affiliation(s)
- Stelvio Sestini
- Deptartment of Diagnostic Imaging, Nuclear Medicine Unit, N.O.P. - S. Stefano, U.S.L. Toscana Centro, via Suor Niccolina Infermiera 20, 59100, Prato, Italy.
| | - Francesco Pestelli
- Deptartment of Internal Medicine, Cardiovascular Unit, N.O.P. - S. Stefano, U.S.L, Toscana Centro, Prato, Italy
| | - Mario Leoncini
- Deptartment of Internal Medicine, Cardiovascular Unit, N.O.P. - S. Stefano, U.S.L, Toscana Centro, Prato, Italy
| | - Francesco Bellandi
- Deptartment of Internal Medicine, Cardiovascular Unit, N.O.P. - S. Stefano, U.S.L, Toscana Centro, Prato, Italy
| | - Christian Mazzeo
- Deptartment of Diagnostic Imaging, Nuclear Medicine Unit, N.O.P. - S. Stefano, U.S.L. Toscana Centro, via Suor Niccolina Infermiera 20, 59100, Prato, Italy
| | - Luigi Mansi
- Deptartment of Diagnostic Imaging, Nuclear Medicine Unit, University II Naples, Naples, Italy
| | - Ignasi Carrio
- Nuclear Medicine, Hospital Sant Pau, Barcelona, Spain
| | - Antonio Castagnoli
- Deptartment of Diagnostic Imaging, Nuclear Medicine Unit, N.O.P. - S. Stefano, U.S.L. Toscana Centro, via Suor Niccolina Infermiera 20, 59100, Prato, Italy
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Buroker NE. Identifying changes in punitive transcriptional factor binding sites from regulatory single nucleotide polymorphisms that are significantly associated with disease or sickness. World J Hematol 2016; 5:75-87. [DOI: 10.5315/wjh.v5.i4.75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/14/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To identify punitive transcriptional factor binding sites (TFBS) from regulatory single nucleotide polymorphisms (rSNPs) that are significantly associated with disease.
METHODS The genome-wide association studies have provided us with nearly 6500 disease or trait-predisposing SNPs where 93% are located within non-coding regions such as gene regulatory or intergenic areas of the genome. In the regulatory region of a gene, a SNP can change the DNA sequence of a transcriptional factor (TF) motif and in turn may affect the process of gene regulation. SNP changes that affect gene expression and impact gene regulatory sequences such as promoters, enhancers, and silencers are known as rSNPs. Computational tools can be used to identify unique punitive TFBS created by rSNPs that are associated with disease or sickness. Computational analysis was used to identify punitive TFBS generated by the alleles of these rSNPs.
RESULTS rSNPs within nine genes that have been significantly associated with disease or sickness were used to illustrate the tremendous diversity of punitive unique TFBS that can be generated by their alleles. The genes studied are the adrenergic, beta, receptor kinase 1, the v-akt murine thymoma viral oncogene homolog 3, the activating transcription factor 3, the type 2 demodkinase gene, the endothetal Per-Arnt-Sim domain protein 1, the lysosomal acid lipase A, the signal Transducer and Activator of Transcription 4, the thromboxane A2 receptor and the vascular endothelial growth factor A. From this sampling of SNPs among the nine genes, there are 73 potential unique TFBS generated by the common alleles compared to 124 generated by the minor alleles indicating the tremendous diversity of potential TFs that are capable of regulating these genes.
CONCLUSION From the diversity of unique punitive binding sites for TFs, it was found that some TFs play a role in the disease or sickness being studied.
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Hackfort BT, Mishra PK. Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases. Am J Physiol Heart Circ Physiol 2016; 310:H802-12. [PMID: 26801305 PMCID: PMC4867357 DOI: 10.1152/ajpheart.00660.2015] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 01/18/2016] [Indexed: 12/15/2022]
Abstract
Despite an obnoxious smell and toxicity at a high dose, hydrogen sulfide (H2S) is emerging as a cardioprotective gasotransmitter. H2S mitigates pathological cardiac remodeling by regulating several cellular processes including fibrosis, hypertrophy, apoptosis, and inflammation. These encouraging findings in rodents led to initiation of a clinical trial using a H2S donor in heart failure patients. However, the underlying molecular mechanisms by which H2S mitigates cardiac remodeling are not completely understood. Empirical evidence suggest that H2S may regulate signaling pathways either by directly influencing a gene in the cascade or interacting with nitric oxide (another cardioprotective gasotransmitter) or both. Recent studies revealed that H2S may ameliorate cardiac dysfunction by up- or downregulating specific microRNAs. MicroRNAs are noncoding, conserved, regulatory RNAs that modulate gene expression mostly by translational inhibition and are emerging as a therapeutic target for cardiovascular disease (CVD). Few microRNAs also regulate H2S biosynthesis. The inter-regulation of microRNAs and H2S opens a new avenue for exploring the H2S-microRNA crosstalk in CVD. This review embodies regulatory mechanisms that maintain the physiological level of H2S, exogenous H2S donors used for increasing the tissue levels of H2S, H2S-mediated regulation of CVD, H2S-microRNAs crosstalk in relation to the pathophysiology of heart disease, clinical trials on H2S, and future perspectives for H2S as a therapeutic agent for heart failure.
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Affiliation(s)
- Bryan T Hackfort
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and
| | - Paras K Mishra
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska
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Zheng W, McKinney W, Kashon M, Salmen R, Castranova V, Kan H. The influence of inhaled multi-walled carbon nanotubes on the autonomic nervous system. Part Fibre Toxicol 2016; 13:8. [PMID: 26864021 PMCID: PMC4750189 DOI: 10.1186/s12989-016-0119-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 02/02/2016] [Indexed: 11/10/2022] Open
Abstract
Background Heart rate and cardiovascular function are regulated by the autonomic nervous system. Heart rate variability (HRV) as a marker reflects the activity of autonomic nervous system. The prognostic significance of HRV in cardiovascular disease has been reported in clinical and epidemiological studies. The present study focused on the influence of inhaled multi-walled carbon nanotubes (MWCNTs) on autonomic nervous system by HRV analysis. Methods Male Sprague–Dawley rats were pre-implanted with a telemetry device and kept in the individual cages for recovery. At week four after device implantation, rats were exposed to MWCNTs for 5 h at a concentration of 5 mg/m3. The real-time EKGs were recorded by a telemetry system at pre-exposure, during exposure, 1 day and 7 days post-exposure. HRV was measured by root mean square of successive differences (RMSSD); the standard deviation of inter-beat (RR) interval (SDNN); the percentage of successive RR interval differences greater than 5 ms (pNN5) and 10 ms (pNN10); low frequency (LF) and high frequency (HF). Results Exposure to MWCNTs increased the percentage of differences between adjacent R-R intervals over 10 ms (pNN10) (p < 0.01), RMSSD (p < 0.01), LF (p < 0.05) and HF (p < 0.01). Conclusions Inhalation of MWCNTs significantly alters the balance between sympathetic and parasympathetic nervous system. Whether such transient alterations in autonomic nervous performance would alter cardiovascular function and raise the risk of cardiovascular events in people with pre-existing cardiovascular conditions warrants further study.
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Affiliation(s)
- W Zheng
- Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
| | - W McKinney
- Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
| | - M Kashon
- Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
| | - R Salmen
- Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
| | - V Castranova
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26505, USA.
| | - H Kan
- Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV, 26505, USA. .,Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, 26505, USA.
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Hu H, Xuan Y, Xue M, Cheng W, Wang Y, Li X, Yin J, Li X, Yang N, Shi Y, Yan S. Semaphorin 3A attenuates cardiac autonomic disorders and reduces inducible ventricular arrhythmias in rats with experimental myocardial infarction. BMC Cardiovasc Disord 2016; 16:16. [PMID: 26787044 PMCID: PMC4719212 DOI: 10.1186/s12872-016-0192-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 01/08/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND To investigate the effects of semaphorin 3A (sema 3A) on cardiac autonomic regulation and subsequent ventricular arrhythmias (VAs) in post-infarcted hearts. METHOD AND RESULTS In order to explore the functions of sema 3A in post-infarcted hearts, lentivirus-Sema 3A-shRNA and negative control vectors were delivered to the peri-infarcted myocardium rats respectively. Meanwhile, recombinant sema 3A and control (0.9% NaCl solution) were injected intravenously into infarcted rats to test the therapeutic potential of sema 3A. Results indicated that levels of sema 3A were higher in post-infarcted hearts compared with sham rats. However, sema 3A silencing leaded to sympathetic hyperinnervation, increased myocardial norepinephrine (NE) content and inducible VAs. Conversely, the intravenous administration of sema 3A to infarcted rats reduced sympathetic nerve sprouting, improved cardiac autonomic regulation, and decreased the incidence of inducible VAs. However, both infarct size and cardiac function were similar among infarcted hearts. CONCLUSIONS The upregulation and administration of sema 3A exerted beneficial effects on infarction-induced cardiac autonomic disorders by increasing cardiac electrical stability and reducing VAs. Sema 3A might be a potential therapeutic agent for cardiac autonomic abnormalities induced arrhythmias.
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Affiliation(s)
- Hesheng Hu
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Yongli Xuan
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Mei Xue
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Wenjuan Cheng
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Ye Wang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Xinran Li
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Jie Yin
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Xiaolu Li
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Na Yang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Yugen Shi
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
| | - Suhua Yan
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, China.
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McCrink KA, Brill A, Lymperopoulos A. Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure. World J Cardiol 2015; 7:539-543. [PMID: 26413230 PMCID: PMC4577680 DOI: 10.4330/wjc.v7.i9.539] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/24/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic (adrenergic) nervous system (SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases (GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell (receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.
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Affiliation(s)
- Katie A McCrink
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
| | - Ava Brill
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
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Ferron AJT, Jacobsen BB, Sant’Ana PG, de Campos DHS, de Tomasi LC, Luvizotto RDAM, Cicogna AC, Leopoldo AS, Lima-Leopoldo AP. Cardiac Dysfunction Induced by Obesity Is Not Related to β-Adrenergic System Impairment at the Receptor-Signalling Pathway. PLoS One 2015; 10:e0138605. [PMID: 26390297 PMCID: PMC4577087 DOI: 10.1371/journal.pone.0138605] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/01/2015] [Indexed: 01/29/2023] Open
Abstract
Obesity has been shown to impair myocardial performance. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them beta-adrenergic (βA) system, an important mechanism of regulation of myocardial contraction and relaxation. The objective of present study was to evaluate the involvement of βA system components in myocardial dysfunction induced by obesity. Thirty-day-old male Wistar rats were distributed in control (C, n = 25) and obese (Ob, n = 25) groups. The C group was fed a standard diet and Ob group was fed four unsaturated high-fat diets for 15 weeks. Cardiac function was evaluated by isolated papillary muscle preparation and βA system evaluated by using cumulative concentrations of isoproterenol and Western blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats and several comorbidities; however, were not associated with changes in systolic blood pressure. Obesity caused structural changes and the myocardial responsiveness to post-rest contraction stimulus and increased extracellular calcium (Ca2+) was compromised. There were no changes in cardiac function between groups after βA stimulation. The obesity was not accompanied by changes in protein expression of G protein subunit alpha (Gsα) and βA receptors (β1AR and β2AR). In conclusion, the myocardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to βAR system impairment at the receptor-signalling pathway.
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Affiliation(s)
- Artur Junio Togneri Ferron
- Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Bruno Barcellos Jacobsen
- Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Paula Grippa Sant’Ana
- Department of Clinical and Cardiology, School of Medicine, UNESP- Univ. Estadual Paulista, Botucatu, São Paulo, Brazil
| | | | - Loreta Casquel de Tomasi
- Department of Clinical and Cardiology, School of Medicine, UNESP- Univ. Estadual Paulista, Botucatu, São Paulo, Brazil
| | | | - Antonio Carlos Cicogna
- Department of Clinical and Cardiology, School of Medicine, UNESP- Univ. Estadual Paulista, Botucatu, São Paulo, Brazil
| | - André Soares Leopoldo
- Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Ana Paula Lima-Leopoldo
- Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
- * E-mail:
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Krasavin M. Biologically active compounds based on the privileged 2-imidazoline scaffold: The world beyond adrenergic/imidazoline receptor modulators. Eur J Med Chem 2015; 97:525-37. [DOI: 10.1016/j.ejmech.2014.11.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/12/2014] [Accepted: 11/14/2014] [Indexed: 01/04/2023]
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Schmieder RE, Mitrovic V, Hengstenberg C. Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin. Clin Res Cardiol 2015; 104:621-31. [PMID: 25787721 DOI: 10.1007/s00392-015-0839-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 03/04/2015] [Indexed: 12/29/2022]
Abstract
Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30-50% of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine-vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.
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Affiliation(s)
- Roland E Schmieder
- Department of Nephrology and Hypertension, University Hospital of the University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany,
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Buroker NE. Regulatory SNPs and transcriptional factor binding sites in ADRBK1, AKT3, ATF3, DIO2, TBXA2R and VEGFA. Transcription 2014; 5:e964559. [PMID: 25483406 PMCID: PMC4581348 DOI: 10.4161/21541264.2014.964559] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract Regulatory single nucleotide polymorphisms (rSNPs) which change the transcriptional factor binding sites (TFBS) for transcriptional factors (TFs) to bind DNA were reviewed for the ADRBK1 (GRK2), AKT3, ATF3, DIO2, TBXA2R and VEGFA genes. Changes in the TFBS where TFs attach to regulate these genes may result in human sickness and disease. The highlights of this previous work were reviewed for these genes.
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Affiliation(s)
- Norman E Buroker
- Department of Pediatrics, University of Washington, Seattle, WA USA
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Rengo G. The adrenergic system in cardiovascular pathophysiology: a translational science point of view. Front Physiol 2014; 5:356. [PMID: 25278905 PMCID: PMC4166352 DOI: 10.3389/fphys.2014.00356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 09/02/2014] [Indexed: 12/22/2022] Open
Affiliation(s)
- Giuseppe Rengo
- Scientific Institute of Telese Terme, Istituto di Ricovero e Cura a Carattere Scientifico, Salvatore Maugeri Foundation Telese Terme, Italy
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de Lucia C, Femminella GD, Gambino G, Pagano G, Allocca E, Rengo C, Silvestri C, Leosco D, Ferrara N, Rengo G. Adrenal adrenoceptors in heart failure. Front Physiol 2014; 5:246. [PMID: 25071591 PMCID: PMC4084669 DOI: 10.3389/fphys.2014.00246] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 06/13/2014] [Indexed: 01/08/2023] Open
Abstract
Heart failure (HF) is a chronic clinical syndrome characterized by the reduction in left ventricular (LV) function and it represents one of the most important causes of morbidity and mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Sympathetic outflow, characterized by increased circulating catecholamines (CA) biosynthesis and secretion, is peculiar in HF and sympatholytic treatments (as β-blockers) are presently being used for the treatment of this disease. Adrenal gland secretes Epinephrine (80%) and Norepinephrine (20%) in response to acetylcholine stimulation of nicotinic cholinergic receptors on the chromaffin cell membranes. This process is regulated by adrenergic receptors (ARs): α2ARs inhibit CA release through coupling to inhibitory Gi-proteins, and β ARs (mainly β2ARs) stimulate CA release through coupling to stimulatory Gs-proteins. All ARs are G-protein-coupled receptors (GPCRs) and GPCR kinases (GRKs) regulate their signaling and function. Adrenal GRK2-mediated α2AR desensitization and downregulation are increased in HF and seem to be a fundamental regulator of CA secretion from the adrenal gland. Consequently, restoration of adrenal α2AR signaling through the inhibition of GRK2 is a fascinating sympatholytic therapeutic strategy for chronic HF. This strategy could have several significant advantages over existing HF pharmacotherapies minimizing side-effects on extra-cardiac tissues and reducing the chronic activation of the renin–angiotensin–aldosterone and endothelin systems. The role of adrenal ARs in regulation of sympathetic hyperactivity opens interesting perspectives in understanding HF pathophysiology and in the identification of new therapeutic targets.
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Affiliation(s)
- Claudio de Lucia
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Grazia D Femminella
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Giuseppina Gambino
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Gennaro Pagano
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Elena Allocca
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Carlo Rengo
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy ; Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme Telese Terme, Italy
| | - Candida Silvestri
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Dario Leosco
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy
| | - Nicola Ferrara
- Department of Medical Translational Sciences, University of Naples Federico II Naples, Italy ; Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme Telese Terme, Italy
| | - Giuseppe Rengo
- Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme Telese Terme, Italy
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Lymperopoulos A, Negussie S. βArrestins in cardiac G protein-coupled receptor signaling and function: partners in crime or "good cop, bad cop"? Int J Mol Sci 2013; 14:24726-24741. [PMID: 24351844 PMCID: PMC3876138 DOI: 10.3390/ijms141224726] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 12/12/2013] [Accepted: 12/13/2013] [Indexed: 12/12/2022] Open
Abstract
βArrestin (βarr)-1 and -2 (βarrs) (or Arrestin-2 and -3, respectively) are universal G protein-coupled receptor (GPCR) adapter proteins expressed abundantly in extra-retinal tissues, including the myocardium. Both were discovered in the lab of the 2012 Nobel Prize in Chemistry co-laureate Robert Lefkowitz, initially as terminators of signaling from the β-adrenergic receptor (βAR), a process known as functional desensitization. They are now known to switch GPCR signaling from G protein-dependent to G protein-independent, which, in the case of βARs and angiotensin II type 1 receptor (AT1R), might be beneficial, e.g., anti-apoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac GPCR signaling and function (or dysfunction in disease), remain unknown. The current consensus is that, whereas both βarr isoforms can desensitize and internalize cardiac GPCRs, they play quite different (even opposing in certain instances) roles in the G protein-independent signaling pathways they initiate in the cardiovascular system, including in the myocardium. The present review will discuss the current knowledge in the field of βarrs and their roles in GPCR signaling and function in the heart, focusing on the three most important, for cardiac physiology, GPCR types (β1AR, β2AR & AT1R), and will also highlight important questions that currently remain unanswered.
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Affiliation(s)
- Anastasios Lymperopoulos
- The Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
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