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Pinz MP, Medeiros I, Carvalho LADC, Meotti FC. Is uric acid a true antioxidant? Identification of uric acid oxidation products and their biological effects. Redox Rep 2025; 30:2498105. [PMID: 40415203 DOI: 10.1080/13510002.2025.2498105] [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] [Indexed: 05/27/2025] Open
Abstract
Uric acid (UA), the final product of purine metabolism in humans, exhibits a dual role as an anti or pro-oxidant, depending on the microenvironment. The two-electron oxidation of UA by biological oxidants can neutralize such harmful molecules. Additionally, UA chelates metals and can activate adaptive response against oxidation. However, some products of the reaction between UA and oxidants are not inert and, therefore, do not confer the anticipated antioxidant protection. A direct pro-oxidant effect is favoured in the one-electron oxidation of UA by heme-peroxidases yielding free radical intermediates that can initiate or propagate a radical-chain reaction. Additionally, an indirect pro-oxidant effect has been proposed by eliciting the expression or activation of enzymes that catalyse oxidant production, e.g. NADPH oxidase (NOX). This review brings together fundamental concepts and the molecular mechanisms of the redox reactions involving UA. The signature metabolites from these reactions are discussed to give valuable insights on whether these intermediates are being formed and what role they may play in disease pathogenesis. It proposes that, through identifying specific products, it may be possible to elucidate whether a harmful or protective action is linked to downstream bioactivities.
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Affiliation(s)
- Mikaela Peglow Pinz
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Isadora Medeiros
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Larissa Anastácio da Costa Carvalho
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Flavia Carla Meotti
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
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Thakur MR, Tupe RS. l-Arginine: A multifaceted regulator of diabetic cardiomyopathy. Biochem Biophys Res Commun 2025; 761:151720. [PMID: 40186920 DOI: 10.1016/j.bbrc.2025.151720] [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: 02/14/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.
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Affiliation(s)
- Muskan R Thakur
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, 412115, Maharashtra, India
| | - Rashmi S Tupe
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, 412115, Maharashtra, India.
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3
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Alonazi AS, Almodawah S, Aldigi R, Bin Dayel A, Alamin M, Almotairi AR, El-Tohamy MF, Alharbi H, Ali R, Alshammari TK, Alrasheed NM. Potential cardioprotective effect of paroxetine against ventricular remodeling in an animal model of myocardial infarction: a comparative study. BMC Pharmacol Toxicol 2024; 25:99. [PMID: 39696491 DOI: 10.1186/s40360-024-00824-9] [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: 07/20/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Post-myocardial infarction (MI) remodeling involves various structural and functional changes, such as inflammation and fibrosis. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is linked to the progression of cardiovascular diseases, including myocardial infarction. The inhibitory effects of paroxetine on GRK2 are recognized, yet its protective effect on post-MI remodeling has not been elucidated. Here, we investigated the cardioprotective effect of paroxetine in an animal model of MI, focusing on post-MI cardiac remodeling and comparing its effect to a β-blocker and an angiotensin receptor antagonist. METHODS Albino Wistar rats were divided into five groups (control; untreated MI; and MI pre-treated with either paroxetine, metoprolol, or irbesartan). MI was induced using isoproterenol (100 mg.kg-1) on days 16 and 17. Cardioprotective effects were determined by assessing markers of cardiac injury, histopathology, inflammation, oxidative stress, and fibrosis. Statistical analysis performed using a one-way analysis of variance, followed by an appropriate post hoc test, the differences between the groups were considered significant when the (P < 0.05). RESULTS Paroxetine significantly attenuated cardiac injury biomarkers including serum Tn-I and CK-MB levels. In terms of cardiac remodeling, paroxetine significantly reduced the relative HW/BW index and the plasms FGF23 level. Furthermore, it modulated markers of fibrosis, inflammation, and oxidative stress. CONCLUSION The current findings suggest that pre-treatment with paroxetine may exert a beneficial effect that protects against post-MI remodeling, including modulating fibrotic, inflammatory, and angiogenesis-related factors. Therefore, the current findings show the promising role of paroxetine as a cardioprotective that attenuates post-MI remodeling processes.
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Affiliation(s)
- Asma S Alonazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
| | - Sara Almodawah
- College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Rana Aldigi
- College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Anfal Bin Dayel
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Maha Alamin
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad R Almotairi
- Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Maha F El-Tohamy
- Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hana Alharbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Rehab Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Tahani K Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nouf M Alrasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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4
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Shao Z, Ding X, Zhou Y, Zhou J, Luo Y, Wu D, Dai Y, Qian L, Wang R, Yu Z. The role and mechanism of P2X7R in cirrhotic cardiomyopathy. Mol Immunol 2024; 176:49-59. [PMID: 39577339 DOI: 10.1016/j.molimm.2024.11.007] [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: 08/03/2024] [Revised: 11/07/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024]
Abstract
In the context of liver cirrhosis, the incidence of myocardial inflammation and apoptosis escalates, contributing to the development and progression of cirrhotic cardiomyopathy. The P2X7 receptor, a purinergic receptor linked to inflammatory processes, has been identified in the etiology of a range of autoinflammatory, autoimmune, chronic inflammatory, and metabolic disorders. Despite this, the specific role of the P2X7 receptor in the etiology of cirrhotic cardiomyopathy remains to be elucidated. In our research, a cirrhotic cardiomyopathy animal model was established using mice subjected to bile duct ligation. The expression of the P2X7 receptor was suppressed via intraperitoneal administration of Brilliant Blue G. Cardiac function was evaluated using echocardiographic techniques, while histopathological examination and enzyme-linked immunosorbent assays were employed to assess the presence of inflammation and apoptosis in liver and cardiac tissues. The expression of key proteins, including P2X7, NLRP3, and IL-1β, in the myocardial tissue was quantified by Western blot analysis. Our research has unveiled significant findings in a murine model of liver fibrosis induced by two weeks of bile duct ligation. Notably, we detected escalated levels of liver fibrosis coupled with disruptions in liver blood flow dynamics. Concurrently, there was a marked increase in myocardial inflammation and apoptosis, which adversely affected heart function. Intriguingly, the expression of P2X7 receptors (P2X7R) in cardiac and hepatic tissues was found to be significantly elevated. Targeting and inhibiting the expression of P2X7R not only alleviated myocardial inflammation and apoptosis but also enhanced cardiac performance. Furthermore, this intervention resulted in a noticeable reduction in liver fibrosis. The interplay between the P2X7 and NLRP3 pathways emerges as a pivotal mechanism in the etiology and progression of cirrhotic cardiomyopathy. Our findings suggest that modulating the P2X7-NLRP3 axis could offer promising therapeutic avenues for managing cirrhotic cardiomyopathy.
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Affiliation(s)
- Zhenhao Shao
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Xu Ding
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Yiting Zhou
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Jiabin Zhou
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Yu Luo
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Dan Wu
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Yufei Dai
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Lingling Qian
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Ruxing Wang
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China
| | - Zhiming Yu
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China; Wuxi People's Hospital, Wuxi, China.
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5
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Chen S, Wang Q, Bakker D, Hu X, Zhang L, van der Made I, Tebbens AM, Kovácsházi C, Giricz Z, Brenner GB, Ferdinandy P, Schaart G, Gemmink A, Hesselink MKC, Rivaud MR, Pieper MP, Hollmann MW, Weber NC, Balligand JL, Creemers EE, Coronel R, Zuurbier CJ. Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2. Basic Res Cardiol 2024; 119:751-772. [PMID: 39046464 PMCID: PMC11461573 DOI: 10.1007/s00395-024-01067-9] [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: 03/05/2024] [Revised: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 07/25/2024]
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.
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Affiliation(s)
- Sha Chen
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Qian Wang
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Diane Bakker
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Xin Hu
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Liping Zhang
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, USA
| | - Ingeborg van der Made
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Anna M Tebbens
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Csenger Kovácsházi
- HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089, Budapest, Hungary
| | - Zoltán Giricz
- HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089, Budapest, Hungary
- Pharmahungary Group, 6722, Szeged, Hungary
| | - Gábor B Brenner
- HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089, Budapest, Hungary
| | - Peter Ferdinandy
- HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089, Budapest, Hungary
- Pharmahungary Group, 6722, Szeged, Hungary
| | - Gert Schaart
- Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Anne Gemmink
- Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Matthijs K C Hesselink
- Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Mathilde R Rivaud
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Michael P Pieper
- CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany
| | - Markus W Hollmann
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Nina C Weber
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Jean-Luc Balligand
- Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC) and Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Esther E Creemers
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ruben Coronel
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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6
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Gebeyehu GM, Rashidiani S, Farkas B, Szabadi A, Brandt B, Pap M, Rauch TA. Unveiling the Role of Exosomes in the Pathophysiology of Sepsis: Insights into Organ Dysfunction and Potential Biomarkers. Int J Mol Sci 2024; 25:4898. [PMID: 38732114 PMCID: PMC11084308 DOI: 10.3390/ijms25094898] [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: 04/03/2024] [Revised: 04/25/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Extracellular vesicles (EVs) are tools for intercellular communication, mediating molecular transport processes. Emerging studies have revealed that EVs are significantly involved in immune processes, including sepsis. Sepsis, a dysregulated immune response to infection, triggers systemic inflammation and multi-organ dysfunction, posing a life-threatening condition. Although extensive research has been conducted on animals, the complex inflammatory mechanisms that cause sepsis-induced organ failure in humans are still not fully understood. Recent studies have focused on secreted exosomes, which are small extracellular vesicles from various body cells, and have shed light on their involvement in the pathophysiology of sepsis. During sepsis, exosomes undergo changes in content, concentration, and function, which significantly affect the metabolism of endothelia, cardiovascular functions, and coagulation. Investigating the role of exosome content in the pathogenesis of sepsis shows promise for understanding the molecular basis of human sepsis. This review explores the contributions of activated immune cells and diverse body cells' secreted exosomes to vital organ dysfunction in sepsis, providing insights into potential molecular biomarkers for predicting organ failure in septic shock.
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Affiliation(s)
- Gizaw Mamo Gebeyehu
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary; (G.M.G.); (S.R.); (B.F.)
| | - Shima Rashidiani
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary; (G.M.G.); (S.R.); (B.F.)
| | - Benjámin Farkas
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary; (G.M.G.); (S.R.); (B.F.)
| | - András Szabadi
- Department of Dentistry, Oral and Maxillofacial Surgery, Medical School, University of Pécs, 7623 Pécs, Hungary;
| | - Barbara Brandt
- Hungary Department of Medical Biology and Central Electron Microscope Laboratory, Medical School, University of Pécs, 7624 Pécs, Hungary; (B.B.); (M.P.)
| | - Marianna Pap
- Hungary Department of Medical Biology and Central Electron Microscope Laboratory, Medical School, University of Pécs, 7624 Pécs, Hungary; (B.B.); (M.P.)
| | - Tibor A. Rauch
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary; (G.M.G.); (S.R.); (B.F.)
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7
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Kuroshima T, Kawaguchi S, Okada M. Current Perspectives of Mitochondria in Sepsis-Induced Cardiomyopathy. Int J Mol Sci 2024; 25:4710. [PMID: 38731929 PMCID: PMC11083471 DOI: 10.3390/ijms25094710] [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: 03/24/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt β-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.
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Affiliation(s)
| | | | - Motoi Okada
- Department of Emergency Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (T.K.); (S.K.)
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Angelone T, Rocca C, Lionetti V, Penna C, Pagliaro P. Expanding the Frontiers of Guardian Antioxidant Selenoproteins in Cardiovascular Pathophysiology. Antioxid Redox Signal 2024; 40:369-432. [PMID: 38299513 DOI: 10.1089/ars.2023.0285] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
Significance: Physiological levels of reactive oxygen and nitrogen species (ROS/RNS) function as fundamental messengers for many cellular and developmental processes in the cardiovascular system. ROS/RNS involved in cardiac redox-signaling originate from diverse sources, and their levels are tightly controlled by key endogenous antioxidant systems that counteract their accumulation. However, dysregulated redox-stress resulting from inefficient removal of ROS/RNS leads to inflammation, mitochondrial dysfunction, and cell death, contributing to the development and progression of cardiovascular disease (CVD). Recent Advances: Basic and clinical studies demonstrate the critical role of selenium (Se) and selenoproteins (unique proteins that incorporate Se into their active site in the form of the 21st proteinogenic amino acid selenocysteine [Sec]), including glutathione peroxidase and thioredoxin reductase, in cardiovascular redox homeostasis, representing a first-line enzymatic antioxidant defense of the heart. Increasing attention has been paid to emerging selenoproteins in the endoplasmic reticulum (ER) (i.e., a multifunctional intracellular organelle whose disruption triggers cardiac inflammation and oxidative stress, leading to multiple CVD), which are crucially involved in redox balance, antioxidant activity, and calcium and ER homeostasis. Critical Issues: This review focuses on endogenous antioxidant strategies with therapeutic potential, particularly selenoproteins, which are very promising but deserve more detailed and clinical studies. Future Directions: The importance of selective selenoproteins in embryonic development and the consequences of their mutations and inborn errors highlight the need to improve knowledge of their biological function in myocardial redox signaling. This could facilitate the development of personalized approaches for the diagnosis, prevention, and treatment of CVD. Antioxid. Redox Signal. 40, 369-432.
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Affiliation(s)
- Tommaso Angelone
- Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, Italy
- National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Carmine Rocca
- Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, Italy
| | - Vincenzo Lionetti
- Unit of Translational Critical Care Medicine, Laboratory of Basic and Applied Medical Sciences, Interdisciplinary Research Center "Health Science," Scuola Superiore Sant'Anna, Pisa, Italy
- UOSVD Anesthesiology and Intensive Care Medicine, Fondazione Toscana "Gabriele Monasterio," Pisa, Italy
| | - Claudia Penna
- National Institute of Cardiovascular Research (INRC), Bologna, Italy
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
| | - Pasquale Pagliaro
- National Institute of Cardiovascular Research (INRC), Bologna, Italy
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
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9
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Aktay I, Bitirim CV, Olgar Y, Durak A, Tuncay E, Billur D, Akcali KC, Turan B. Cardioprotective role of a magnolol and honokiol complex in the prevention of doxorubicin-mediated cardiotoxicity in adult rats. Mol Cell Biochem 2024; 479:337-350. [PMID: 37074505 DOI: 10.1007/s11010-023-04728-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 04/02/2023] [Indexed: 04/20/2023]
Abstract
Doxorubicin (DOXO) induces marked cardiotoxicity, though increased oxidative stress while there are some documents related with cardioprotective effects of some antioxidants against organ-toxicity during cancer treatment. Although magnolia bark has some antioxidant-like effects, its action in DOXO-induced heart dysfunction has not be shown clearly. Therefore, here, we aimed to investigate the cardioprotective action of a magnolia bark extract with active component magnolol and honokiol complex (MAHOC; 100 mg/kg) in DOXO-treated rat hearts. One group of adult male Wistar rats was injected with DOXO (DOXO-group; a cumulative dose of 15 mg/kg in 2-week) or saline (CON-group). One group of DOXO-treated rats was administered with MAHOC before DOXO (Pre-MAHOC group; 2-week) while another group was administered with MAHOC following the 2-week DOXO (Post-MAHOC group). MAHOC administration, before or after DOXO, provided full survival of animals during 12-14 weeks, and significant recoveries in the systemic parameters of animals such as plasma levels of manganese and zinc, total oxidant and antioxidant statuses, and also systolic and diastolic blood pressures. This treatment also significantly improved heart function including recoveries in end-diastolic volume, left ventricular end-systolic volume, heart rate, cardiac output, and prolonged P-wave duration. Furthermore, the MAHOC administrations improved the structure of left ventricles such as recoveries in loss of myofibrils, degenerative nuclear changes, fragmentation of cardiomyocytes, and interstitial edema. Biochemical analysis in the heart tissues provided the important cardioprotective effect of MAHOC on the redox regulation of the heart, such as improvements in activities of glutathione peroxidase and glutathione reductase, and oxygen radical-absorbing capacity of the heart together with recoveries in other systemic parameters of animals, while all of these benefits were observed in the Pre-MAHOC treatment group, more prominently. Overall, one can point out the beneficial antioxidant effects of MAHOC in chronic heart diseases as a supporting and complementing agent to the conventional therapies.
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Affiliation(s)
- Irem Aktay
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Ceylan Verda Bitirim
- Stem Cell Institute, Ankara University, Ankara, Turkey
- Ankara University Stem cell Institute, Ankara, Turkey
| | - Yusuf Olgar
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Aysegul Durak
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Erkan Tuncay
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Deniz Billur
- Department of Histology and Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Kamil Can Akcali
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
| | - Belma Turan
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
- Department of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey.
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10
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Srivastava P, Sudevan ST, Thennavan A, Mathew B, Kanthlal SK. Inhibiting Monoamine Oxidase in CNS and CVS would be a Promising Approach to Mitigating Cardiovascular Complications in Neurodegenerative Disorders. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:331-341. [PMID: 36872357 DOI: 10.2174/1871527322666230303115236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 12/17/2022] [Accepted: 01/03/2023] [Indexed: 03/07/2023]
Abstract
The flavoenzyme monoamine oxidases (MAOs) are present in the mitochondrial outer membrane and are responsible for the metabolism of biogenic amines. MAO deamination of biological amines produces toxic byproducts such as amines, aldehydes, and hydrogen peroxide, which are significant in the pathophysiology of multiple neurodegenerative illnesses. In the cardiovascular system (CVS), these by-products target the mitochondria of cardiac cells leading to their dysfunction and producing redox imbalance in the endothelium of the blood vessels. This brings up the biological relationship between the susceptibility of getting cardiovascular disorders in neural patients. In the current scenario, MAO inhibitors are highly recommended by physicians worldwide for the therapy and management of various neurodegenerative disorders. Many interventional studies reveal the benefit of MAO inhibitors in CVS. Drug candidates who can target both the central and peripheral MAO could be a better to compensate for the cardiovascular comorbidities observed in neurodegenerative patients.
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Affiliation(s)
- Princika Srivastava
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, 682 041, Kerala, India
| | - Sachithra Thazhathuveedu Sudevan
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India
| | - Arumugam Thennavan
- Central Lab Animal Facility, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, 682 041, Kerala, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India
| | - S K Kanthlal
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, 682 041, Kerala, India
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11
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Wang Y, Luo Y, Yang S, Jiang M, Chu Y. LC-MS/MS-Based Serum Metabolomics and Transcriptome Analyses for the Mechanism of Augmented Renal Clearance. Int J Mol Sci 2023; 24:10459. [PMID: 37445637 DOI: 10.3390/ijms241310459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 07/15/2023] Open
Abstract
Augmented Renal Clearance (ARC) refers to the increased renal clearance of circulating solute in critically ill patients. In this study, the analytical research method of transcriptomics combined with metabolomics was used to study the pathogenesis of ARC at the transcriptional and metabolic levels. In transcriptomics, 534 samples from 5 datasets in the Gene Expression Omnibus database were analyzed and 834 differential genes associated with ARC were obtained. In metabolomics, we used Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry to determine the non-targeted metabolites of 102 samples after matching propensity scores, and obtained 45 differential metabolites associated with ARC. The results of the combined analysis showed that purine metabolism, arginine biosynthesis, and arachidonic acid metabolism were changed in patients with ARC. We speculate that the occurrence of ARC may be related to the alteration of renal blood perfusion by LTB4R, ARG1, ALOX5, arginine and prostaglandins E2 through inflammatory response, as well as the effects of CA4, PFKFB2, PFKFB3, PRKACB, NMDAR, glutamate and cAMP on renal capillary wall permeability.
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Affiliation(s)
- Yidan Wang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Yifan Luo
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Shu Yang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Mingyan Jiang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Yang Chu
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
- School of Pharmacy, China Medical University, Shenyang 110122, China
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12
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Uribe P, Barra J, Painen K, Zambrano F, Schulz M, Moya C, Isachenko V, Isachenko E, Mallmann P, Sánchez R. FeTPPS, a Peroxynitrite Decomposition Catalyst, Ameliorates Nitrosative Stress in Human Spermatozoa. Antioxidants (Basel) 2023; 12:1272. [PMID: 37372002 DOI: 10.3390/antiox12061272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Excessive levels of reactive nitrogen species (RNS), such as peroxynitrite, promote nitrosative stress, which is an important cause of impaired sperm function. The metalloporphyrin FeTPPS is highly effective in catalyzing the decomposition of peroxynitrite, reducing its toxic effects in vivo and in vitro. FeTPPS has significant therapeutic potential in peroxynitrite-related diseases; however, its effects on human spermatozoa under nitrosative stress have not been described. This work aimed to evaluate the in vitro effect of FeTPPS against peroxynitrite-mediated nitrosative stress in human spermatozoa. For this purpose, spermatozoa from normozoospermic donors were exposed to 3-morpholinosydnonimine, a molecule that generates peroxynitrite. First, the FeTPPS-mediated peroxynitrite decomposition catalysis was analyzed. Then, its individual effect on sperm quality parameters was evaluated. Finally, the effect of FeTPPS on ATP levels, motility, mitochondrial membrane potential, thiol oxidation, viability, and DNA fragmentation was analyzed in spermatozoa under nitrosative stress conditions. The results showed that FeTPPS effectively catalyzes the decomposition of peroxynitrite without affecting sperm viability at concentrations up to 50 μmol/L. Furthermore, FeTPPS mitigates the deleterious effects of nitrosative stress on all sperm parameters analyzed. These results highlight the therapeutic potential of FeTPPS in reducing the negative impact of nitrosative stress in semen samples with high RNS levels.
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Affiliation(s)
- Pamela Uribe
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
- Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4781176, Chile
| | - Javiera Barra
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
| | - Kevin Painen
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
| | - Fabiola Zambrano
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
- Department of Preclinical Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4781176, Chile
| | - Mabel Schulz
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
- Department of Preclinical Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4781176, Chile
| | - Claudia Moya
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
| | - Vladimir Isachenko
- Research Group in Reproductive Medicine, Department of Obstetrics and Gynecology, Cologne University, 50923 Köln, Germany
| | - Evgenia Isachenko
- Research Group in Reproductive Medicine, Department of Obstetrics and Gynecology, Cologne University, 50923 Köln, Germany
| | - Peter Mallmann
- Research Group in Reproductive Medicine, Department of Obstetrics and Gynecology, Cologne University, 50923 Köln, Germany
| | - Raúl Sánchez
- Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
- Department of Preclinical Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4781176, Chile
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13
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Nisa FY, Rahman MA, Rafi MKJ, Khan MAN, Sultana F, Majid M, Hossain MA, Deen JI, Mannan M, Saha S, Tangpong J, Choudhury TR. Biosynthesized magnesium oxide nanoparticles from Tamarindus indica seed attenuate doxorubicin-induced cardiotoxicity by regulating biochemical indexes and linked genes. BIOMATERIALS ADVANCES 2023; 146:213291. [PMID: 36709628 DOI: 10.1016/j.bioadv.2023.213291] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 06/09/2023]
Abstract
The phytochemicals of Tamarindus indica seed hydroalcoholic extract were exploited as a biocatalyst for the sustainable synthesis of magnesium oxide nanoparticles (MgO-NPs). This research investigated the cardioprotective effects of biosynthesized magnesium oxide nanoparticle (MgO-NPs). The biosynthesized seed MgO-NPs were characterized by ultraviolet-visible spectroscopy (UV-Vis), X-ray diffraction (XRD), scanning electron microscopy (SEM) with energy-dispersive X-ray diffraction (EDX), and Fourier-transform infrared spectroscopy (FT-IR). These methodological approaches demonstrated their capacity to synthesize crystalline and aggregated MgO-NPs with a size average of 13.38 ± 0.16 nm. The biogenic MgO-NPs were found to have a significant quantity of total phenolic contents (TPC) and total flavonoid contents (TFC), indicating the existence of phenol and flavonoid-like components. The biogenic MgO-NPs demonstrated a significant free radical scavenging effects compared to different standards as measured by the inhibition of free radicals produced in 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS•+), and Nitric oxide (NO) scavenging methods; they also exhibited higher ferric ion reducing capacity in FRAP assay. Moreover, they were found to be non-toxic in cytotoxic assessment. Pretreatment of Wistar Albino rats with seed MgO-NPs resulted in a significant reduction of cardiac biomarkers, i.e., cardiac Troponin-I (cTnI), creatine kinase (CK-MB), and aspartate aminotransferase (AST). The seed MgO-NPs were more successful in reducing lipid levels. The results of the mRNA expression analysis showed that seed MgO-NPs efficiently reduced the expression of the apoptotic genes p53 and Caspase-3 while restoring the expected levels of SOD gene expression. The histopathological observations were primarily focused on the disruption of cardiac fibers and myofibrillar disintegration, which are consistent with the biochemical findings. Therefore, our research suggests that MgO-NPs derived from the seeds of Tamarindus indica as a powerful antioxidant; the administration may be effective in protecting the heart from DOX-induced cardiotoxicity.
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Affiliation(s)
- Fatema Yasmin Nisa
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Md Atiar Rahman
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand.
| | - Md Khalid Juhani Rafi
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Md Asif Nadim Khan
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Farjana Sultana
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Mumtahina Majid
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Md Altaf Hossain
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Jobaier Ibne Deen
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Md Mannan
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Srabonti Saha
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh.
| | - Jitbanjong Tangpong
- School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand.
| | - Tasrina Rabia Choudhury
- Analytical Chemistry Laboratory, Chemistry Division, Atomic Energy Centre Dhaka, Bangladesh Atomic Energy Commission, Bangladesh
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14
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Gergely TG, Kucsera D, Tóth VE, Kovács T, Sayour NV, Drobni ZD, Ruppert M, Petrovich B, Ágg B, Onódi Z, Fekete N, Pállinger É, Buzás EI, Yousif LI, Meijers WC, Radovits T, Merkely B, Ferdinandy P, Varga ZV. Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment. Br J Pharmacol 2023; 180:740-761. [PMID: 36356191 DOI: 10.1111/bph.15984] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 10/06/2022] [Accepted: 10/29/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. EXPERIMENTAL APPROACH C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. KEY RESULTS Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. CONCLUSIONS PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.
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Affiliation(s)
- Tamás G Gergely
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Dániel Kucsera
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Viktória E Tóth
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Tamás Kovács
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Nabil V Sayour
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Zsófia D Drobni
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Mihály Ruppert
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Balázs Petrovich
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bence Ágg
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary.,MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zsófia Onódi
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Nóra Fekete
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Edit I Buzás
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Laura I Yousif
- Department of Cardiology, Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Wouter C Meijers
- Department of Cardiology, Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary.,MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.,MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
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15
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Al-Kouh A, Babiker F, Al-Bader M. Renin-Angiotensin System Antagonism Protects the Diabetic Heart from Ischemia/Reperfusion Injury in Variable Hyperglycemia Duration Settings by a Glucose Transporter Type 4-Mediated Pathway. Pharmaceuticals (Basel) 2023; 16:238. [PMID: 37259385 PMCID: PMC9967344 DOI: 10.3390/ph16020238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/15/2023] [Accepted: 02/01/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a risk factor for cardiovascular diseases, specifically, the ischemic heart diseases (IHD). The renin-angiotensin system (RAS) affects the heart directly and indirectly. However, its role in the protection of the heart against I/R injury is not completely understood. The aim of the current study was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor and Angiotensin II receptor (AT1R) blocker or a combination thereof in protection of the heart from I/R injury. METHODS Hearts isolated from adult male Wistar rats (n = 8) were subjected to high glucose levels; acute hyperglycemia or streptozotocin (STZ)-induced diabetes were used in this study. Hearts were subjected to I/R injury, treated with Captopril, an ACE inhibitor; Losartan, an AT1R antagonist; or a combination thereof. Hemodynamics data were measured using a suitable software for that purpose. Additionally, infarct size was evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The levels of apoptosis markers (caspase-3 and -8), antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), nitric oxide synthase (eNOS), and glucose transporter type 4 (GLUT-4) protein levels were evaluated by Western blotting. Pro-inflammatory and anti-inflammatory cytokines levels were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS Captopril and Losartan alone or in combination abolished the effect of I/R injury in hearts subjected to acute hyperglycemia or STZ-induced diabetes. There was a significant (p < 0.05) recovery in hemodynamics, infarct size, and apoptosis markers following the treatment with Captopril, Losartan, or their combination. Treatment with Captopril, Losartan, or their combination significantly (p < 0.05) reduced pro-inflammatory cytokines and increased GLUT-4 protein levels. CONCLUSIONS The blockade of the RAS system protected the diabetic heart from I/R injury. This protection followed a pathway that utilizes GLUT-4 to decrease the apoptosis markers, pro-inflammatory cytokines, and to increase the anti-inflammatory cytokines. This protection seems to employ a pathway which is not involving ERK1/2 and eNOS.
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Affiliation(s)
| | - Fawzi Babiker
- Department of Physiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Kuwait City 13110, Kuwait
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16
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da Silva ML, de Sousa Neto IV, de Lima ACGB, Barin F, de Toledo Nóbrega O, de Cássia Marqueti R, Cipriano GFB, Durigan JLQ, Ferreira EA, Bottaro M, Arena R, Cahalin LP, Neder JA, Junior GC. Effects of Home-Based Electrical Stimulation on Plasma Cytokines Profile, Redox Biomarkers, and Metalloproteinases in the Heart Failure with Reduced Ejection Fraction: A Randomized Trial. J Cardiovasc Dev Dis 2022; 9:jcdd9120463. [PMID: 36547460 PMCID: PMC9785395 DOI: 10.3390/jcdd9120463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/01/2022] [Accepted: 10/20/2022] [Indexed: 12/23/2022] Open
Abstract
Background: Low-frequency electrical stimulation (LFES) is an adjuvant method for heart failure (HF) patients with restrictions to start an exercise. However, the impact on molecular changes in circulating is unknown. We investigated the effects of 10 weeks of home-based LFES on plasma cytokines profile, redox biomarkers, metalloproteinases (MMPs) activity, and exercise performance in HF patients. Methods: Twenty-four HF patients (52.45 ± 9.15 years) with reduced ejection fraction (HFrEF) (EF < 40%), were randomly assigned to a home-based LFES or sham protocol. Plasma cytokines profile was assessed through interleukins, interferon-gamma, and tumor necrosis factor levels. Oxidative stress was evaluated through ferric reducing antioxidant power, thiobarbituric acid-reactive substances, and inducible nitric oxide synthase. The MMPs activity were analyzed by zymography. Cardiorespiratory capacity and muscle strength were evaluated by cardiopulmonary test and isokinetic. Results: LFES was able to increase the active-MMP2 activity post compared to pre-training (0.057 to 0.163, p = 0.0001), while it decreased the active-MMP9 (0.135 to 0.093, p = 0.02). However, it did not elicit changes in cytokines, redox biomarkers, or exercise performance (p > 0.05). Conclusion: LFES protocol is a promising intervention to modulate MMPs activity in HFrEF patients, although with limited functional effects. These preliminary responses may help the muscle to adapt to future mechanical demands dynamically.
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Affiliation(s)
- Marianne Lucena da Silva
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
- Health Sciences Academic Unit, Federal University of Jataí, Jataí 75801-615, GO, Brazil
| | - Ivo Vieira de Sousa Neto
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Alexandra C. G. B. de Lima
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Fabrício Barin
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Otávio de Toledo Nóbrega
- Department of Medicine, University of Brasilia (UnB), Campus Universitário Darcy Ribeiro, Asa Norte, Brasilia 70910-900, DF, Brazil
| | - Rita de Cássia Marqueti
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Graziella F. B. Cipriano
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - João Luiz Quagliotti Durigan
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Eduardo Antônio Ferreira
- Department of Pharmacy, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
| | - Martim Bottaro
- Department of Physical Education, University of Brasilia (UnB), Campus Universitário Darcy Ribeiro, Asa Norte, Brasilia 70910-900, DF, Brazil
| | - Ross Arena
- Department of Physical Therapy, University of Illinois, 1919 W Taylor St., Chicago, IL 60612, USA
| | - Larry P. Cahalin
- Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, 5915 Ponce de Leon Blvd., 5th Floor, Coral Gables, FL 33101, USA
| | - José Alberto Neder
- Department of Medicine, School of Medicine at the Queen’s University, Queen’s University & Kingston General Hospital, Etherington Hall, Rooms 3032-3043, 94 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Gerson Cipriano Junior
- Rehabilitation Sciences and Health Sciences and Technologies Ph.D. Program, University of Brasilia (UnB), Campus Universitário, s/n, Centro Metropolitano, Brasilia 72220-275, DF, Brazil
- Correspondence:
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17
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de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022; 74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 195] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
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Affiliation(s)
- Luiz G N de Almeida
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Hayley Thode
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Yekta Eslambolchi
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sameeksha Chopra
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Daniel Young
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sean Gill
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Laurent Devel
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Antoine Dufour
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
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18
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Mitochondrial Side Effects of Surgical Prophylactic Antibiotics Ceftriaxone and Rifaximin Lead to Bowel Mucosal Damage. Int J Mol Sci 2022; 23:ijms23095064. [PMID: 35563455 PMCID: PMC9103148 DOI: 10.3390/ijms23095064] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/28/2022] [Accepted: 04/30/2022] [Indexed: 02/04/2023] Open
Abstract
Despite their clinical effectiveness, a growing body of evidence has shown that many classes of antibiotics lead to mitochondrial dysfunction. Ceftriaxone and Rifaximin are first choice perioperative antibiotics in gastrointestinal surgery targeting fundamental processes of intestinal bacteria; however, may also have negative consequences for the host cells. In this study, we investigated their direct effect on mitochondrial functions in vitro, together with their impact on ileum, colon and liver tissue. Additionally, their impact on the gastrointestinal microbiome was studied in vivo, in a rat model. Rifaximin significantly impaired the oxidative phosphorylation capacity (OxPhos) and leak respiration in the ileal mucosa, in line with increased oxidative tissue damage and histological changes following treatment. Ceftriaxone prophylaxis led to similar changes in the colon mucosa. The composition and diversity of bacterial communities differed extensively in response to antibiotic pre-treatment. However, the relative abundances of the toxin producing species were not increased. We have confirmed the harmful effects of prophylactic doses of Rifaximin and Ceftriaxone on the intestinal mucosa and that these effects were related to the mitochondrial dysfunction. These experiments raise awareness of mitochondrial side effects of these antibiotics that may be of clinical importance when evaluating their adverse effects on bowel mucosa.
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19
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Mongirdienė A, Skrodenis L, Varoneckaitė L, Mierkytė G, Gerulis J. Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies. Biomedicines 2022; 10:602. [PMID: 35327404 PMCID: PMC8945343 DOI: 10.3390/biomedicines10030602] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
With respect to structural and functional cardiac disorders, heart failure (HF) is divided into HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Oxidative stress contributes to the development of both HFrEF and HFpEF. Identification of a broad spectrum of reactive oxygen species (ROS)-induced pathways in preclinical models has provided new insights about the importance of ROS in HFrEF and HFpEF development. While current treatment strategies mostly concern neuroendocrine inhibition, recent data on ROS-induced metabolic pathways in cardiomyocytes may offer additional treatment strategies and targets for both of the HF forms. The purpose of this article is to summarize the results achieved in the fields of: (1) ROS importance in HFrEF and HFpEF pathophysiology, and (2) treatments for inhibiting ROS-induced pathways in HFrEF and HFpEF patients. ROS-producing pathways in cardiomyocytes, ROS-activated pathways in different HF forms, and treatment options to inhibit their action are also discussed.
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Affiliation(s)
- Aušra Mongirdienė
- Department of Biochemistry, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50161 Kaunas, Lithuania
| | - Laurynas Skrodenis
- Medical Academy, Lithuanian University of Health Sciences, Mickevičiaus str. 9, LT-44307 Kaunas, Lithuania
| | - Leila Varoneckaitė
- Medical Academy, Lithuanian University of Health Sciences, Mickevičiaus str. 9, LT-44307 Kaunas, Lithuania
| | - Gerda Mierkytė
- Medical Academy, Lithuanian University of Health Sciences, Mickevičiaus str. 9, LT-44307 Kaunas, Lithuania
| | - Justinas Gerulis
- Medical Academy, Lithuanian University of Health Sciences, Mickevičiaus str. 9, LT-44307 Kaunas, Lithuania
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20
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Peluffo RD. Cationic amino acid transporters and their modulation by nitric oxide in cardiac muscle cells. Biophys Rev 2022; 13:1071-1079. [PMID: 35059028 DOI: 10.1007/s12551-021-00870-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/22/2021] [Indexed: 01/03/2023] Open
Abstract
Cationic amino acid transporters (CATs) play a central role in the supply of the substrate L-arginine to intracellular nitric oxide synthases (NOS), the enzymes responsible for the synthesis of nitric oxide (NO). In heart, NO produced by cardiac myocytes has diverse and even opposite effects on myocardial contractility depending on the subcellular location of its production. Approximately a decade ago, using a combination of biophysical and biochemical approaches, we discovered and characterized high- and low-affinity CATs that function simultaneously in the cardiac myocyte plasma membrane. Later on, we reported a negative feedback regulation of NO on the activity of cardiac CATs. In this way, NO was found to modulate its own biosynthesis by regulating the amount of L-arginine that becomes available as NOS substrate. We have recently solved the molecular determinants for this NO regulation on the low-affinity high-capacity CAT-2A. This review highlights some biophysical and biochemical features of L-arginine transporters and their potential relation to cardiac muscle physiology and pathology.
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Affiliation(s)
- R Daniel Peluffo
- Group of Biophysical Chemistry, Department of Biological Sciences, CENUR Litoral Norte, Universidad de La República, Rivera 1350, CP: 50000 Salto, Uruguay.,Department of Pharmacology, Physiology and Neuroscience, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103 USA
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21
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Kawaguchi S, Okada M. Cardiac Metabolism in Sepsis. Metabolites 2021; 11:metabo11120846. [PMID: 34940604 PMCID: PMC8707959 DOI: 10.3390/metabo11120846] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/11/2022] Open
Abstract
The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.
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Affiliation(s)
- Satoshi Kawaguchi
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Bloomington, IN 46202, USA;
| | - Motoi Okada
- Department of Emergency Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
- Correspondence: ; Tel.: +81-166-68-2852
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22
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Weissman D, Maack C. Redox signaling in heart failure and therapeutic implications. Free Radic Biol Med 2021; 171:345-364. [PMID: 34019933 DOI: 10.1016/j.freeradbiomed.2021.05.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/17/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022]
Abstract
Heart failure is a growing health burden worldwide characterized by alterations in excitation-contraction coupling, cardiac energetic deficit and oxidative stress. While current treatments are mostly limited to antagonization of neuroendocrine activation, more recent data suggest that also targeting metabolism may provide substantial prognostic benefit. However, although in a broad spectrum of preclinical models, oxidative stress plays a causal role for the development and progression of heart failure, no treatment that targets reactive oxygen species (ROS) directly has entered the clinical arena yet. In the heart, ROS derive from various sources, such as NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase and mitochondria. While mitochondria are the primary source of ROS in the heart, communication between different ROS sources may be relevant for physiological signalling events as well as pathologically elevated ROS that deteriorate excitation-contraction coupling, induce hypertrophy and/or trigger cell death. Here, we review the sources of ROS in the heart, the modes of pathological activation of ROS formation as well as therapeutic approaches that may target ROS specifically in mitochondria.
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Affiliation(s)
- David Weissman
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany; Department of Internal Medicine 1, University Clinic Würzburg, Würzburg, Germany.
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23
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Maeda K, Hotta Y, Ieda N, Kataoka T, Nakagawa H, Kimura K. Control of rat bladder neck relaxation with NORD-1, a red light-reactive nitric oxide releaser: In vitro study. J Pharmacol Sci 2021; 146:226-232. [PMID: 34116736 DOI: 10.1016/j.jphs.2021.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/01/2021] [Accepted: 03/23/2021] [Indexed: 01/06/2023] Open
Abstract
We aimed to control the relaxation of rat bladder neck specimens by using NORD-1, a red light-reactive nitric oxide (NO) releaser. Female and male 10-11-week-old Wistar/ST rats were divided into three groups: NORD-1, vehicle, and NORD-1+[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor). We infused 10-4 M NORD-1 into the bladders of NORD-1 and NORD-1+ODQ group rats and the vehicle into those of vehicle group rats. Isometric tension was analyzed using circular bladder neck specimens with 10-5 M NG-nitro-l-arginine methyl ester, an NO synthase inhibitor. Moreover, 10-5 M ODQ was added into the NORD-1+ODQ group bath. After precontraction with 10-5 M carbachol, the specimens were irradiated with red light and their relaxation responses were measured. We evaluated NORD-1 tissue permeability by observing the sliced bladder neck specimens. The NORD-1 group specimens relaxed during red light irradiation; the relaxation response increased with the increase in light intensity. The vehicle and NORD-1+ODQ group specimens did not respond to irradiation. Sex-related differences in responsiveness were not noted. NORD-1 permeated into the urothelium of NORD-1 group specimens. Rat bladder neck relaxation was controlled by NORD-1 and light irradiation in vitro. NORD-1 might be a novel therapeutic agent for voiding dysfunction.
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Affiliation(s)
- Kotomi Maeda
- Department of Hospital Pharmacy, Nagoya City University, Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8603, Japan.
| | - Yuji Hotta
- Department of Hospital Pharmacy, Nagoya City University, Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8603, Japan.
| | - Naoya Ieda
- Department of Organic and Medicinal Chemistry, Nagoya City University, Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8603, Japan.
| | - Tomoya Kataoka
- Department of Clinical Pharmaceutics, Nagoya City University, Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8601, Japan.
| | - Hidehiko Nakagawa
- Department of Organic and Medicinal Chemistry, Nagoya City University, Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8603, Japan.
| | - Kazunori Kimura
- Department of Hospital Pharmacy, Nagoya City University, Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8603, Japan; Department of Clinical Pharmaceutics, Nagoya City University, Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya-shi, Aichi-ken 467-8601, Japan.
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24
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Ghionzoli N, Gentile F, Del Franco AM, Castiglione V, Aimo A, Giannoni A, Burchielli S, Cameli M, Emdin M, Vergaro G. Current and emerging drug targets in heart failure treatment. Heart Fail Rev 2021; 27:1119-1136. [PMID: 34273070 PMCID: PMC9197912 DOI: 10.1007/s10741-021-10137-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 12/11/2022]
Abstract
After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin–angiotensin–aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.
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Affiliation(s)
- Nicolò Ghionzoli
- Department of Medical Biotechnologies, Division of Cardiology, University of Siena, Siena, Italy
| | | | - Anna Maria Del Franco
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, 1 - 56124, Pisa, Italy
| | | | - Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alberto Giannoni
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, 1 - 56124, Pisa, Italy
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | | | - Matteo Cameli
- Department of Medical Biotechnologies, Division of Cardiology, University of Siena, Siena, Italy
| | - Michele Emdin
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, 1 - 56124, Pisa, Italy
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Giuseppe Vergaro
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, 1 - 56124, Pisa, Italy.
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
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25
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Mohammadi A, Balizadeh Karami AR, Dehghan Mashtani V, Sahraei T, Bandani Tarashoki Z, Khattavian E, Mobarak S, Moradi Kazerouni H, Radmanesh E. Evaluation of Oxidative Stress, Apoptosis, and Expression of MicroRNA-208a and MicroRNA-1 in Cardiovascular Patients. Rep Biochem Mol Biol 2021; 10:183-196. [PMID: 34604408 PMCID: PMC8480300 DOI: 10.52547/rbmb.10.2.183] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 02/15/2021] [Indexed: 04/25/2023]
Abstract
BACKGROUND MicroRNA expression signature and reactive oxygen species (ROS) production have been associated with the development of cardiovascular diseases (CVDs). This study aimed to evaluate oxidative stress, inflammation, apoptosis, and the expression of miRNA-208a and miRNA-1 in cardiovascular patients. METHODS The study population included four types of patients (acute coronary syndromes (ACS), myocardial infarction (MI), arrhythmia, and heart failure (HF)), with 10 people in each group, as well as a control group. Quantitative real-time PCR was performed to measure mir-208 and miR-1 expression, the mRNAs of inflammatory mediators (TNFα, iNOS/eNOS), and apoptotic factors (Bax and Bcl2). XOX, MDA, and antioxidant enzymes (CAT, SOD, and GPx) were measured by ZellBio GmbH kits by an ELISA Reader. RESULTS The results showed significant decreases in the activity of antioxidant enzymes (CAT, SOD, and Gpx) and a significant increase in the activity of the MDA and XOX in cardiovascular patients. Significant increases in IL-10, iNos, iNOS / eNOS, and TNF-α in cardiovascular patients were also observed. Also, a significant increase in the expression of miR-208 (HF> arrhythmia> ACS> MI) and a significant decrease in the expression of miR-1 (ACS> arrhythmia> HF> MI) were found in all four groups in cardiovascular patients. CONCLUSION The results showed increases in oxidative stress, inflammation, apoptotic factors, and in the expression of miR-208a in a variety of cardiovascular patients (ACS, MI, arrhythmia, and HF). It is suggested that future studies determine the relationships that miR-1, miR-208, and oxidative stress indices have with inflammation and apoptosis.
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Affiliation(s)
| | | | | | | | | | - Ehsan Khattavian
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran.
| | - Sara Mobarak
- Abadan Faculty of Medical Sciences, Abadan, Iran.
| | | | - Esmat Radmanesh
- Abadan Faculty of Medical Sciences, Abadan, Iran.
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran.
- Corresponding author: Esmat Radmanesh; Tel: +98 9171438307; E-mail:
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26
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Baik AH, Oluwole OO, Johnson DB, Shah N, Salem JE, Tsai KK, Moslehi JJ. Mechanisms of Cardiovascular Toxicities Associated With Immunotherapies. Circ Res 2021; 128:1780-1801. [PMID: 33934609 PMCID: PMC8159878 DOI: 10.1161/circresaha.120.315894] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immune-based therapies have revolutionized cancer treatments. Cardiovascular sequelae from these treatments, however, have emerged as critical complications, representing new challenges in cardio-oncology. Immune therapies include a broad range of novel drugs, from antibodies and other biologics, including immune checkpoint inhibitors and bispecific T-cell engagers, to cell-based therapies, such as chimeric-antigen receptor T-cell therapies. The recognition of immunotherapy-associated cardiovascular side effects has also catapulted new research questions revolving around the interactions between the immune and cardiovascular systems, and the signaling cascades affected by T cell activation, cytokine release, and immune system dysregulation. Here, we review the specific mechanisms of immune activation from immunotherapies and the resulting cardiovascular toxicities associated with immune activation and excess cytokine production.
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Affiliation(s)
- Alan H Baik
- Division of Cardiovascular Medicine, Department of Medicine, UCSF, San Francisco, CA (A.H.B.)
| | - Olalekan O Oluwole
- Division of Oncology (D.B.J., J.J.M., O.O.O.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Douglas B Johnson
- Division of Oncology (D.B.J., J.J.M., O.O.O.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Nina Shah
- Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA (N.S., K.K.T.)
| | - Joe-Elie Salem
- Department of Pharmacology, Cardio-oncology Program, CIC-1901, APHP.Sorbonne Université, Paris, France (J.-E.S.)
- Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.-E.S., J.J.M.)
| | - Katy K Tsai
- Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA (N.S., K.K.T.)
| | - Javid J Moslehi
- Division of Cardiovascular Medicine (J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Division of Oncology (D.B.J., J.J.M., O.O.O.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.-E.S., J.J.M.)
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27
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Varghese SS, Eekhoudt CR, Jassal DS. Mechanisms of anthracycline-mediated cardiotoxicity and preventative strategies in women with breast cancer. Mol Cell Biochem 2021; 476:3099-3109. [PMID: 33835331 DOI: 10.1007/s11010-021-04152-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/01/2021] [Indexed: 12/17/2022]
Abstract
While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.
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Affiliation(s)
- Sonu S Varghese
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Cameron R Eekhoudt
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Davinder S Jassal
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. .,Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada. .,Department of Radiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
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Yin D, Ji C, Zhang S, Wang J, Lu Z, Song X, Jiang H, Lau WY, Liu L. Clinical characteristics and management of 1572 patients with pyogenic liver abscess: A 12-year retrospective study. Liver Int 2021; 41:810-818. [PMID: 33314531 PMCID: PMC8048845 DOI: 10.1111/liv.14760] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Pyogenic liver abscesses (PLA) are space-occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. METHODS Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. RESULTS Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006-2011 to 1,239 (78.8%) in 2012-2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P = .035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. CONCLUSIONS Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes.
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Affiliation(s)
- Dalong Yin
- Department of Hepatobiliary SurgeryThe First Affiliated HospitalDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
| | - Changyong Ji
- Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Shugeng Zhang
- Department of Hepatobiliary SurgeryThe First Affiliated HospitalDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina,Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Jiabei Wang
- Department of Hepatobiliary SurgeryThe First Affiliated HospitalDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
| | - Zhaoyang Lu
- Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xuan Song
- Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Hongchi Jiang
- Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Wan Yee Lau
- Faculty of Medicinethe Chinese University of Hong KongHong Kong SARChina
| | - Lianxin Liu
- Department of Hepatobiliary SurgeryThe First Affiliated HospitalDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina,Department of Liver SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
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29
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Shyni GL, Renjitha J, B Somappa S, Raghu KG. Zerumin A attenuates the inflammatory responses in LPS-stimulated H9c2 cardiomyoblasts. J Biochem Mol Toxicol 2021; 35:1-11. [PMID: 33755281 DOI: 10.1002/jbt.22777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/21/2020] [Accepted: 03/12/2021] [Indexed: 11/07/2022]
Abstract
Zerumin A (ZA) is one of the potential components of Curcuma amada rhizomes, and it has been shown to possess a variety of pharmacological activities. This study deals with the beneficial activity of ZA in lipopolysaccharide (LPS)-stimulated inflammation in H9c2 cardiomyoblasts. Herein, H9c2 cells were preincubated with ZA for 1 h and stimulated with LPS for 24 h. The cells were analyzed for the expression of various pro-inflammatory mediators and signaling molecules. Results showed that the cell viability was significantly improved and reactive oxygen species production was alleviated remarkably with ZA pretreatment. We also found that ZA pretreatment significantly suppressed the upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein levels, and nitric oxide (NO) release in LPS-stimulated cells. In addition, ZA significantly ameliorated LPS-elicited overexpression of pro-inflammatory chemokines and cytokines such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF- α), interferon-γ (IFN-γ), and interleukin-1 (IL-1) in H9c2 cells, and it upregulated the synthesis of the anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, pretreatment with ZA and the mitogen-activated protein kinases (MAPK) pathway inhibitors also reduced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK), and p38. ZA significantly inhibited IkB-a phosphorylation and nuclear factor (NF)-kB p65 subunit translocation into nuclei. Overall data demonstrated that ZA protects cardiomyocytes against LPS injury by inhibiting NF-kB p65 activation via the MAPK signaling pathway in vitro. These findings suggest that ZA may be a promising agent for a detailed study for the prevention or treatment of myocardial dysfunction in sepsis.
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Affiliation(s)
- G L Shyni
- Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India
| | - J Renjitha
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India
| | - Sasidhar B Somappa
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India
| | - K G Raghu
- Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India
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30
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Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J 2021; 288:7162-7182. [PMID: 33405316 DOI: 10.1111/febs.15701] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/14/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that were first discovered as proteases, which target and cleave extracellular proteins. During the past 20 years, however, intracellular roles of MMPs were uncovered and research on this new aspect of their biology expanded. MMP-2 is the first of this protease family to be reported to play a crucial intracellular role where it cleaves several sarcomeric proteins inside cardiac myocytes during oxidative stress-induced injury. Beyond MMP-2, currently at least eleven other MMPs are known to function intracellularly including MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-23 and MMP-26. These intracellular MMPs are localized to different compartments inside the cell including the cytosol, sarcomere, mitochondria, and the nucleus. Intracellular MMPs contribute to the pathogenesis of various diseases. Cardiovascular renal disorders, inflammation, and malignancy are some examples. They also exert antiviral and bactericidal effects. Interestingly, MMPs can act intracellularly through both protease-dependent and protease-independent mechanisms. In this review, we will highlight the intracellular mechanisms of MMPs activation, their numerous subcellular locales, substrates, and roles in different pathological conditions. We will also discuss the future direction of MMP research and the necessity to exploit the knowledge of their intracellular targets and actions for the design of targeted inhibitors.
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Affiliation(s)
- Wesam Bassiouni
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Mohammad A M Ali
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, State University of New York-Binghamton, NY, USA
| | - Richard Schulz
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
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31
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Scheen M, Giraud R, Bendjelid K. Stress hyperglycemia, cardiac glucotoxicity, and critically ill patient outcomes current clinical and pathophysiological evidence. Physiol Rep 2021; 9:e14713. [PMID: 33463901 PMCID: PMC7814494 DOI: 10.14814/phy2.14713] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/09/2020] [Accepted: 12/12/2020] [Indexed: 01/07/2023] Open
Abstract
Stress hyperglycemia is a transient increase in blood glucose during acute physiological stress in the absence of glucose homeostasis dysfunction. Its's presence has been described in critically ill patients who are subject to many physiological insults. In this regard, hyperglycemia and impaired glucose tolerance are also frequent in patients who are admitted to the intensive care unit for heart failure and cardiogenic shock. The hyperglycemia observed at the beginning of these cardiac disorders appears to be related to a variety of stress mechanisms. The release of major stress and steroid hormones, catecholamine overload, and glucagon all participate in generating a state of insulin resistance with increased hepatic glucose output and glycogen breakdown. In fact, the observed pathophysiological response, which appears to regulate a stress situation, is harmful because it induces mitochondrial impairment, oxidative stress-related injury to cells, endothelial damage, and dysfunction of several cellular channels. Paradigms are now being challenged by growing evidence of a phenomenon called glucotoxicity, providing an explanation for the benefits of lowering glucose levels with insulin therapy in these patients. In the present review, the authors present the data published on cardiac glucotoxicity and discuss the benefits of lowering plasma glucose to improve heart function and to positively affect the course of critical illness.
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Affiliation(s)
- Marc Scheen
- Intensive Care DivisionUniversity HospitalsGenevaSwitzerland
- Geneva Hemodynamic Research GroupGenevaSwitzerland
- Faculty of MedicineGenevaSwitzerland
| | - Raphael Giraud
- Intensive Care DivisionUniversity HospitalsGenevaSwitzerland
- Geneva Hemodynamic Research GroupGenevaSwitzerland
- Faculty of MedicineGenevaSwitzerland
| | - Karim Bendjelid
- Intensive Care DivisionUniversity HospitalsGenevaSwitzerland
- Geneva Hemodynamic Research GroupGenevaSwitzerland
- Faculty of MedicineGenevaSwitzerland
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32
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Murao A, Brenner M, Aziz M, Wang P. Exosomes in Sepsis. Front Immunol 2020; 11:2140. [PMID: 33013905 PMCID: PMC7509534 DOI: 10.3389/fimmu.2020.02140] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 08/06/2020] [Indexed: 12/13/2022] Open
Abstract
Sepsis is a severe state of infection with high mortality. Pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) initiate dysregulated systemic inflammation upon binding to pattern recognition receptors. Exosomes are endosome-derived vesicles, which carry proteins, lipids and nucleic acids, and facilitate intercellular communications. Studies have shown altered contents and function of exosomes during sepsis. In sepsis, exosomes carry increased levels of cytokines and DAMPs to induce inflammation. Exosomal DAMPs include, but are not limited to, high mobility group box 1, heat shock proteins, histones, adenosine triphosphate, and extracellular RNA. Exosomes released during sepsis have impact on multiple organs, including the lungs, kidneys, liver, cardiovascular system, and central nervous system. Here, we review the mechanisms of inflammation caused by exosomes, and their contribution to multiple organ dysfunction in sepsis.
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Affiliation(s)
- Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
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33
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Shen Z, Guo Z, Tan T, Hu J, Zhang Y. Reactive Oxygen Species Scavenging and Biodegradable Peptide Hydrogel as 3D Culture Scaffold for Cardiomyocytes. ACS Biomater Sci Eng 2020; 6:3957-3966. [PMID: 33463334 DOI: 10.1021/acsbiomaterials.0c00340] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Myocardial ischemia-reperfusion produces a large amount of reactive oxygen species (ROS), which damage the myocardial tissue. Therefore, localized scavenging of ROS from the myocardial tissue would reduce its damage and avoid metabolic abnormalities caused by systemic ROS. In this study, a free radical scavenging and biodegradable supramolecular peptide (ECAFF, named as ECF-5) hydrogel was designed as a culture scaffold for cardiomyocytes. The peptide hydrogel significantly preserved the migration and proliferation of cardiomyocytes and reduced their damage from oxidative stress. In addition, the hydrogel degraded during cell growth, which implies that it may avoid thrombosis of the capillaries in practical use and provide the opportunity for the cells to attach to each other and form a functional tissue. The hydrogel can be used as a 3D culture scaffold for cardiomyocyte culture and allow cardiomyocytes to grow into tissue-like cell spheres. The excellent nature of the ECF-5 hydrogel enables it to have broad applications in the biomedical field in the future.
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Affiliation(s)
- Zhiwei Shen
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhen Guo
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tingyuan Tan
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jun Hu
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.,Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Yi Zhang
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.,Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
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34
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Ospina-Tascón GA, Calderón-Tapia LE. Inodilators in septic shock: should these be used? ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:796. [PMID: 32647721 PMCID: PMC7333155 DOI: 10.21037/atm.2020.04.43] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Septic shock involves a complex interaction between abnormal vasodilation, relative and/or absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution to the tissues. Fluid administration, vasopressor support and inotropes, represent fundamental pieces of quantitative resuscitation protocols directed to assist the restoration of impaired tissue perfusion during septic shock. Indeed, current recommendations on sepsis management include the use of inotropes in the case of myocardial dysfunction, as suggested by a low cardiac output, increased filling pressures, or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and mean arterial pressure by fluid administration and vasopressor support. Evidence supporting the use of inotropes in sepsis and septic shock is mainly based on physiological studies. Most of them suggest a beneficial effect of inotropes on macro hemodynamics especially when sepsis coexists with myocardial dysfunction; others, however, have demonstrated variable results on regional splanchnic circulation, while others suggest favorable effects on microvascular distribution independently of its impact on cardiac output. Conversely, impact of inodilators on clinical outcomes in this context has been more controversial. Use of dobutamine has not been consistently related with more favorable clinical results, while systematic administration of levosimendan in sepsis do not prevent the development of multiorgan dysfunction, even in patients with evidence of myocardial dysfunction. Nevertheless, a recent metanalysis of clinical studies suggests that cardiovascular support regimens based on inodilators in sepsis and septic shock could provide some beneficial effect on mortality, while other one corroborated such effect on mortality specially in patients with proved lower cardiac output. Thus, using or not inotropes during sepsis and septic shock remains as controversy matter that deserves more research efforts.
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Affiliation(s)
- Gustavo A Ospina-Tascón
- Department of Intensive Care, Fundación Valle del Lili-Universidad Icesi, Cali, Colombia.,Translational Medicine in Critical Care and Experimental Surgery Laboratory, Universidad Icesi, Cali, Colombia
| | - Luis E Calderón-Tapia
- Department of Intensive Care, Fundación Valle del Lili-Universidad Icesi, Cali, Colombia.,Translational Medicine in Critical Care and Experimental Surgery Laboratory, Universidad Icesi, Cali, Colombia
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35
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Pérez-Torres I, Manzano-Pech L, Rubio-Ruíz ME, Soto ME, Guarner-Lans V. Nitrosative Stress and Its Association with Cardiometabolic Disorders. Molecules 2020; 25:molecules25112555. [PMID: 32486343 PMCID: PMC7321091 DOI: 10.3390/molecules25112555] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023] Open
Abstract
Reactive nitrogen species (RNS) are formed when there is an abnormal increase in the level of nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) and/or by the uncoupled endothelial nitric oxide synthase (eNOS). The presence of high concentrations of superoxide anions (O2−) is also necessary for their formation. RNS react three times faster than O2− with other molecules and have a longer mean half life. They cause irreversible damage to cell membranes, proteins, mitochondria, the endoplasmic reticulum, nucleic acids and enzymes, altering their activity and leading to necrosis and to cell death. Although nitrogen species are important in the redox imbalance, this review focuses on the alterations caused by the RNS in the cellular redox system that are associated with cardiometabolic diseases. Currently, nitrosative stress (NSS) is implied in the pathogenesis of many diseases. The mechanisms that produce damage remain poorly understood. In this paper, we summarize the current knowledge on the participation of NSS in the pathology of cardiometabolic diseases and their possible mechanisms of action. This information might be useful for the future proposal of anti-NSS therapies for cardiometabolic diseases.
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Affiliation(s)
- Israel Pérez-Torres
- Vascular Biomedicine Department, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
- Correspondence: (I.P.-T.); (V.G.-L.)
| | - Linaloe Manzano-Pech
- Vascular Biomedicine Department, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - María Esther Rubio-Ruíz
- Physiology Department, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - María Elena Soto
- Immunology Department, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - Verónica Guarner-Lans
- Physiology Department, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
- Correspondence: (I.P.-T.); (V.G.-L.)
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Matyas C, Erdelyi K, Trojnar E, Zhao S, Varga ZV, Paloczi J, Mukhopadhyay P, Nemeth BT, Haskó G, Cinar R, Rodrigues RM, Ahmed YA, Gao B, Pacher P. Interplay of Liver-Heart Inflammatory Axis and Cannabinoid 2 Receptor Signaling in an Experimental Model of Hepatic Cardiomyopathy. Hepatology 2020; 71:1391-1407. [PMID: 31469200 PMCID: PMC7048661 DOI: 10.1002/hep.30916] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 08/23/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid-2 receptor (CB2 -R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function. APPROACH AND RESULTS BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin-1, P-selectin, cluster of differentiation 45-positive cells); and oxidative stress (increased malondialdehyde, 3-nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB2 -R up-regulation was observed in both livers and hearts of mice exposed to BDL. CB2 -R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB2 -R activation also decreased serum tumor necrosis factor-alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy. CONCLUSIONS We propose BDL-induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver-heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB2 -R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.
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Affiliation(s)
- Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Katalin Erdelyi
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Suxian Zhao
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Zoltan V. Varga
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
- ZVV’s present affiliation: HCEMM-SU Cardiometabolic Immunology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Janos Paloczi
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Partha Mukhopadhyay
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Balazs T. Nemeth
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY 10032, USA
| | - Resat Cinar
- Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Robim M. Rodrigues
- Laboratory of Liver Diseases, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
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38
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Huai Y, Hossen MN, Wilhelm S, Bhattacharya R, Mukherjee P. Nanoparticle Interactions with the Tumor Microenvironment. Bioconjug Chem 2019; 30:2247-2263. [PMID: 31408324 PMCID: PMC6892461 DOI: 10.1021/acs.bioconjchem.9b00448] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Compared to normal tissues, the tumor microenvironment (TME) has a number of aberrant characteristics including hypoxia, acidosis, and vascular abnormalities. Many researchers have sought to exploit these anomalous features of the TME to develop anticancer therapies, and several nanoparticle-based cancer therapeutics have resulted. In this Review, we discuss the composition and pathophysiology of the TME, introduce nanoparticles (NPs) used in cancer therapy, and address the interaction between the TME and NPs. Finally, we outline both the potential problems that affect TME-based nanotherapy and potential strategies to overcome these challenges.
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Affiliation(s)
- Yanyan Huai
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Md Nazir Hossen
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Stefan Wilhelm
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma 73072, United States
| | - Resham Bhattacharya
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Priyabrata Mukherjee
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
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Munkanatta Godage DNP, VanHecke GC, Samarasinghe KTG, Feng HZ, Hiske M, Holcomb J, Yang Z, Jin JP, Chung CS, Ahn YH. SMYD2 glutathionylation contributes to degradation of sarcomeric proteins. Nat Commun 2018; 9:4341. [PMID: 30337525 PMCID: PMC6194001 DOI: 10.1038/s41467-018-06786-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 09/23/2018] [Indexed: 12/22/2022] Open
Abstract
Reactive oxygen species (ROS) contribute to the etiology of multiple muscle-related diseases. There is emerging evidence that cellular stress can lead to destabilization of sarcomeres, the contractile unit of muscle. However, it is incompletely understood how cellular stress induces structural destabilization of sarcomeres. Here we report that glutathionylation of SMYD2 contributes to a loss of myofibril integrity and degradation of sarcomeric proteins mediated by MMP-2 and calpain 1. We used a clickable glutathione approach in a cardiomyocyte cell line and found selective glutathionylation of SMYD2 at Cys13. Biochemical analysis demonstrated that SMYD2 upon oxidation or glutathionylation at Cys13 loses its interaction with Hsp90 and N2A, a domain of titin. Upon dissociation from SMYD2, N2A or titin is degraded by activated MMP-2, suggesting a protective role of SMYD2 in sarcomere stability. Taken together, our results support that SMYD2 glutathionylation is a novel molecular mechanism by which ROS contribute to sarcomere destabilization.
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Affiliation(s)
| | - Garrett C VanHecke
- Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA
| | | | - Han-Zhong Feng
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Mark Hiske
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Joshua Holcomb
- Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Zhe Yang
- Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Jian-Ping Jin
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Charles S Chung
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Young-Hoon Ahn
- Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA.
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González-Montero J, Brito R, Gajardo AIJ, Rodrigo R. Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities. World J Cardiol 2018; 10:74-86. [PMID: 30344955 PMCID: PMC6189069 DOI: 10.4330/wjc.v10.i9.74] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/27/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.
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Affiliation(s)
- Jaime González-Montero
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
| | - Roberto Brito
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Abraham IJ Gajardo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
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Trichosanthis Pericarpium Aqueous Extract Protects H9c2 Cardiomyocytes from Hypoxia/Reoxygenation Injury by Regulating PI3K/Akt/NO Pathway. Molecules 2018; 23:molecules23102409. [PMID: 30241309 PMCID: PMC6222483 DOI: 10.3390/molecules23102409] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/18/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
Trichosanthis Pericarpium (TP) is a traditional Chinese medicine for treating cardiovascular diseases. In this study, we investigated the effects of TP aqueous extract (TPAE) on hypoxia/reoxygenation (H/R) induced injury in H9c2 cardiomyocytes and explored the underlying mechanisms. H9c2 cells were cultured under the hypoxia condition induced by sodium hydrosulfite for 30 min and reoxygenated for 4 h. Cell viability was measured by MTT assay. The amounts of LDH, NO, eNOS, and iNOS were tested by ELISA kits. Apoptotic rate was detected by Annexin V-FITC/PI staining. QRT-PCR was performed to analyze the relative mRNA expression of Akt, Bcl-2, Bax, eNOS, and iNOS. Western blotting was used to detect the expression of key members in the PI3K/Akt pathway. Results showed that the pretreatment of TPAE remarkably enhanced cell viability and decreased apoptosis induced by H/R. Moreover, TPAE decreased the release of LDH and expression of iNOS. In addition, TPAE increased NO production and Bcl-2/Bax ratio. Furthermore, the mRNA and protein expression of p-Akt and eNOS were activated by TPAE pretreatment. On the contrary, a specific inhibitor of PI3K, LY294002 not only inhibited TPAE-induced p-Akt/eNOS upregulation but alleviated its anti-apoptotic effects. In conclusion, results indicated that TPAE protected against H/R injury in cardiomyocytes, which consequently activated the PI3K/Akt/NO signaling pathway.
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Peña-Juarez RA, Garrido-García LM, Zapata-Martínez SG. Miocardiopatía séptica en pacientes pediátricos: fisiopatología y presentación clínica. ACTA COLOMBIANA DE CUIDADO INTENSIVO 2018; 18:179-189. [DOI: 10.1016/j.acci.2018.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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43
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The role of nitric oxide in diabetic skin (patho)physiology. Mech Ageing Dev 2018; 172:21-29. [DOI: 10.1016/j.mad.2017.08.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 08/18/2017] [Accepted: 08/28/2017] [Indexed: 01/29/2023]
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Dkhil MA, Kassab RB, Al-Quraishy S, Abdel-Daim MM, Zrieq R, Abdel Moneim AE. Ziziphus spina-christi (L.) leaf extract alleviates myocardial and renal dysfunction associated with sepsis in mice. Biomed Pharmacother 2018; 102:64-75. [PMID: 29549730 DOI: 10.1016/j.biopha.2018.03.032] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 03/06/2018] [Accepted: 03/06/2018] [Indexed: 02/06/2023] Open
Abstract
Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, has been used by Egyptians (Bedouin and Nubian) to treat inflammatory symptoms and swellings, pain, and heat since long. We aimed to investigate whether Ziziphus spina-christi leaf extract (ZSCLE) exerted a myocardial and renal protective effect on mice in which sepsis had been induced with cecal ligation and puncture (CLP). Male C57BL/6 mice were divided randomly into six groups (n = 7): sham-operated group, sham-operated mice treated with ZSCLE (300 mg/kg), CLP-induced sepsis group, ZSCLE (100 mg/kg)-treated group, ZSCLE (200 mg/kg)-treated group, and ZSCLE (300 mg/kg)-treated group. Pretreatment with ZSCLE (100, 200, and 300 mg/kg) restored the normal heart rate (HR); decreased the elevated levels of malondialdehyde; the activity of myeloperoxidase, nitric oxide (NO), and inducible NO synthase; and the expression of nuclear factor kappa B (NF-κB), but increased the content of glutathione and antioxidant enzyme activities in mice with sepsis. Moreover, the results of biochemical analyses and qRT-PCR indicated that ZSCLE treatment lowered the level of cytokines, including tumor necrosis factor alpha and interleukin (IL)-1β. Additionally, ZSCLE reduced myocardial and renal apoptosis by inducing the downregulation of caspase-3 and Bax mRNA and upregulation of the expression of Bcl-2. Based on these results, we suggest that ZSCLE has a protective effect against multiple-organ impairment that follows sepsis. This effect may be attributed to the antioxidant, anti-inflammatory, and anti-apoptotic activities of ZSCLE.
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Affiliation(s)
- Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia; Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt.
| | - Rami B Kassab
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt.
| | - Saleh Al-Quraishy
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
| | - Mohamed M Abdel-Daim
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.
| | - Rafat Zrieq
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia.
| | - Ahmed E Abdel Moneim
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt.
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Khaper N, Bailey CDC, Ghugre NR, Reitz C, Awosanmi Z, Waines R, Martino TA. Implications of disturbances in circadian rhythms for cardiovascular health: A new frontier in free radical biology. Free Radic Biol Med 2018; 119:85-92. [PMID: 29146117 DOI: 10.1016/j.freeradbiomed.2017.11.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/27/2017] [Accepted: 11/08/2017] [Indexed: 01/19/2023]
Abstract
Cell autonomous circadian "clock" mechanisms are present in virtually every organ, and generate daily rhythms that are important for normal physiology. This is especially relevant to the cardiovascular system, for example the circadian mechanism orchestrates rhythms in heart rate, blood pressure, cardiac contractility, metabolism, gene and protein abundance over the 24-h day and night cycles. Conversely, disturbing circadian rhythms (e.g. via shift work, sleep disorders) increases cardiovascular disease risk, and exacerbates cardiac remodelling and worsens outcome. Notably, reactive oxygen species (ROS) are important contributors to heart disease, especially the pathophysiologic damage that occurs after myocardial infarction (MI, heart attack). However, little is known about how the circadian mechanism, or rhythm desynchrony, is involved in these key pathologic stress responses. This review summarizes the current knowledge on circadian rhythms in the cardiovascular system, and the implications of rhythm disturbances for cardiovascular health. Furthermore, we highlight how free radical biology coincides with the pathogenesis of myocardial repair and remodelling after MI, and indicate a role for the circadian system in the oxidative stress pathways in the heart and brain after MI. This fusion of circadian biology with cardiac oxidative stress pathways is novel, and offers enormous potential for improving our understanding and treatment of heart disease.
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Affiliation(s)
- Neelam Khaper
- Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, Canada P7B5E1
| | - Craig D C Bailey
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences/OVC, University of Guelph, Guelph, Ontario, Canada N1G2W1
| | - Nilesh R Ghugre
- Schulich Heart Research Program, Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M4N 3M5
| | - Cristine Reitz
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences/OVC, University of Guelph, Guelph, Ontario, Canada N1G2W1
| | - Zikra Awosanmi
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences/OVC, University of Guelph, Guelph, Ontario, Canada N1G2W1
| | - Ryan Waines
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences/OVC, University of Guelph, Guelph, Ontario, Canada N1G2W1
| | - Tami A Martino
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences/OVC, University of Guelph, Guelph, Ontario, Canada N1G2W1.
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Abstract
Proinflammatory reaction by the body occurs acutely in response to injury that is considered primarily beneficial. However, sustained proinflammatory cytokines observed with chronic pathologies such as metabolic syndrome, cancer, and arthritis are detrimental and in many cases is a major cardiovascular risk factor. Proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor α (TNFα) have long been implicated in cardiovascular risk and considered to be a major underlying cause for heart failure (HF). The failure of the anti-TNFα therapy for HF indicates our elusive understanding on the dichotomous role of proinflammatory cytokines on acutely beneficial effects versus long-term deleterious effects. Despite these well-described observations, less is known about the mechanistic underpinnings of proinflammatory cytokines especially TNFα in pathogenesis of HF. Increasing evidence suggests the existence of an active cross-talk between the TNFα receptor signaling and G-protein-coupled receptors such as β-adrenergic receptor (βAR). Given that βARs are the key regulators of cardiac function, the review will discuss the current state of understanding on the role of proinflammatory cytokine TNFα in regulating βAR function.
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Affiliation(s)
- Maradumane L Mohan
- *Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; and †Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH
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Monteiro VVS, Reis JF, de Souza Gomes R, Navegantes KC, Monteiro MC. Dual Behavior of Exosomes in Septic Cardiomyopathy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 998:101-112. [PMID: 28936735 DOI: 10.1007/978-981-10-4397-0_7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sepsis is one of the main causes of ICU hospitalization worldwide, with a high mortality rate, and is associated with a large number of comorbidities. One of the main comorbidities associated with sepsis is septic cardiomyopathy. This process occurs mainly due to mechanisms of damage in the cardiovascular system that will lead to changes in cardiovascular physiology, such as decreased Ca2+ response, mitochondrial dysfunction and decreased β-adrenergic receptor response. Within this process the exosomes play an important role in the pathophysiology of this disease, in which the exosomal content is related to mechanisms that will trigger its development. After platelet activation through ROS exposition, exosomes containing high concentrations of NADPH are released in heart blood vessels, those exosomes will be internalized in endothelial cells leading to cell death and cardiac dysfunction. On the opposite, exosomes derived from mesenchymal stem cells contain miR-223, that have anti-inflammatory properties, are released in less quantities in septic patients causing an imbalance that leads to cardiac dysfunction.
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Affiliation(s)
| | - Jordano Ferreira Reis
- School of Pharmacy, Health Science Institute, Federal University of Pará/UFPA, Belém, PA, 66075900, Brazil
| | - Rafaelli de Souza Gomes
- Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPA, Belém, PA, 66075900, Brazil
| | - Kely Campos Navegantes
- Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPA, Belém, PA, 66075900, Brazil
| | - Marta Chagas Monteiro
- Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPA, Belém, PA, 66075900, Brazil.
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Okada M, Falcão LFR, Ferez D, Martins JL, Errante PR, Rodrigues FSM, Caricati-Neto A, Marinho M, Fenelon G, Oliveira-Júnior IS. Effect of atenolol pre-treatment in heart damage in a model of intestinal ischemia-reperfusion. Acta Cir Bras 2017; 32:964-972. [PMID: 29236801 DOI: 10.1590/s0102-865020170110000008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 10/22/2017] [Indexed: 01/23/2023] Open
Abstract
PURPOSE To investigate the effects of atenolol in inflammatory mediator and oxidative stress in a myocardial injury by intestinal ischemia/reperfusion in rat model. METHODS Adult Wistar male rats were randomly (n=8), anesthetized and divided in: Sham: submitted to operation only; group SS+IR: intravenous saline infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); group AT+IR: intravenous atenolol infusion (2 mg/kg) following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); and group AT+I+AT+R: intravenous atenolol infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and in the time 45 minutes other atenolol doses were administrated and the artery was open for 120 minutes (reperfusion), all animals were submitted to muscular relaxation for mechanical ventilation. In the end of experiment the animals were euthanized and the hearts tissue were morphology analyzed by histology and malondialdehyde by ELISA, and the plasma were analyzed for tumor necrosis factor-alpha by ELISA. RESULTS The group SS+IR demonstrated the higher malondialdehyde levels when compared with the atenolol treated-groups (p=0.001) in the heart tissue. The tumor necrosis factor-alpha level in plasma decrease in the treated groups when compared with SS+IR group (p=0.001). Histology analyses demonstrate pyknosis, edema, cellular vacuolization, presence of inflammatory infiltrate and band contraction in the heart tissue of the rats. CONCLUSION Atenolol significantly reduce the degree of cardiac damage after intestinal ischemia-reperfusion.
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Affiliation(s)
- Mieko Okada
- Fellow PhD degree, Postgraduate Program in Translational Medicine, Universidade Federal de São Paulo (UNIFESP), Brazil. Acquisition, analysis and interpretation of data; technical procedures; statistical analysis, manuscript writing
| | - Luiz Fernando Reis Falcão
- PhD, Associate Professor, Division of Anesthesia, Pain and Intensive Medicine, Department of Surgery, UNIFESP, Sao Paulo-SP, Brazil. Interpretation of data, statistical analysis, manuscript writing, critical revision
| | - David Ferez
- PhD, Associate Professor, Division of Anesthesia, Pain and Intensive Medicine, Department of Surgery, UNIFESP, Sao Paulo-SP, Brazil. Interpretation of data, critical revision
| | - José Luiz Martins
- PhD, Full Professor, Division of Anesthesia, Pain and Intensive Medicine, Department of Surgery, UNIFESP, Sao Paulo-SP, Brazil. Interpretation of data, manuscript writing, critical revision
| | - Paolo Ruggero Errante
- Fellow PhD degree, Postgraduate Program in Pharmacology, UNIFESP, Sao Paulo-SP, Brazil. Histopathological examinations, analysis of data
| | - Francisco Sandro Menezes Rodrigues
- Fellow PhD degree, Postgraduate Program in Pharmacology, UNIFESP, Sao Paulo-SP, Brazil. Histopathological examinations, analysis of data
| | - Afonso Caricati-Neto
- PhD, Associate Professor, Department of Pharmacology, UNIFESP, Sao Paulo-SP, Brazil. Manuscript writing, critical revision
| | - Márcia Marinho
- PhD, Full Professor, Veterinary Medicine School, UNESP, Araçatuba-SP, Brazil. Biochemistry data analysis, statistical analysis, critical revision
| | - Guilherme Fenelon
- Associate Professor, Division of Cardiology, Department of Surgery, UNIFESP, Sao Paulo-SP, Brazil. Conception and design of the study, manuscript writing, critical revision
| | - Itamar Souza Oliveira-Júnior
- Full Professor, Division of Anesthesia, Pain and Intensive Medicine, Department of Surgery, and Associate Professor, Postgraduate Program in Translational Medicine, UNIFESP, Sao Paulo-SP, Brazil. Conception and design of the study, critical revision, final approval of the version to be published
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Zhang N, Feng H, Liao HH, Chen S, Yang Z, Deng W, Tang QZ. Myricetin attenuated LPS induced cardiac injuryin vivoandin vitro. Phytother Res 2017; 32:459-470. [PMID: 29214686 DOI: 10.1002/ptr.5989] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 09/08/2017] [Accepted: 10/24/2017] [Indexed: 01/06/2023]
Affiliation(s)
- Nan Zhang
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
| | - Hong Feng
- Department of Gerontology; Renmin Hospital of Wuhan University; Wuhan 430060 China
| | - Hai-Han Liao
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
| | - Si Chen
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
| | - Zheng Yang
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
| | - Wei Deng
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
| | - Qi-Zhu Tang
- Department of Cardiology; Renmin Hospital of Wuhan University; Wuhan 430060 China
- Cardiovascular Research Institute; Wuhan University; Wuhan 430060 China
- Hubei Key Laboratory of Cardiology; Wuhan 430060 China
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Sepsis-Induced Cardiomyopathy: Oxidative Implications in the Initiation and Resolution of the Damage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7393525. [PMID: 29057035 PMCID: PMC5625757 DOI: 10.1155/2017/7393525] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 07/14/2017] [Accepted: 08/23/2017] [Indexed: 12/13/2022]
Abstract
Cardiac dysfunction may complicate the course of severe sepsis and septic shock with significant implications for patient's survival. The basic pathophysiologic mechanisms leading to septic cardiomyopathy have not been fully clarified until now. Disease-specific treatment is lacking, and care is still based on supportive modalities. Septic state causes destruction of redox balance in many cell types, cardiomyocytes included. The production of reactive oxygen and nitrogen species is increased, and natural antioxidant systems fail to counterbalance the overwhelming generation of free radicals. Reactive species interfere with many basic cell functions, mainly through destruction of protein, lipid, and nucleic acid integrity, compromising enzyme function, mitochondrial structure and performance, and intracellular signaling, all leading to cardiac contractile failure. Takotsubo cardiomyopathy may result from oxidative imbalance. This review will address the multiple aspects of cardiomyocyte bioenergetic failure in sepsis and discuss potential therapeutic interventions.
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