Editorial

3 pages, 173 KiB

Open AccessEditorial

by Eltyeb Abdelwahid and Katherine Athayde Teixeira de Carvalho

Int. J. Mol. Sci. 2024, 25(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010011 - 19 Dec 2023

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Recently, various molecular bases of heart protection have been discovered and used in many experimental and clinical investigations [...] Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

Research

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19 pages, 2074 KiB

Open AccessArticle

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy

by Jaroslaw Szponar, Erwin Ciechanski, Marta Ostrowska-Lesko, Agnieszka Gorska, Michal Tchorz, Anna Dabrowska, Jaroslaw Dudka, Marek Murias, Michał Kowalczyk, Agnieszka Korga-Plewko and Slawomir Mandziuk

Int. J. Mol. Sci. 2023, 24(12), 10202; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210202 - 15 Jun 2023

Cited by 2 | Viewed by 1136

Abstract

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the [...] Read more.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study’s objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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24 pages, 4033 KiB

Open AccessArticle

Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis

by Sandra Tejedor, Marc Buigues, Hernán González-King, Andreia M. Silva, Nahuel Aquiles García, Niek Dekker and Pilar Sepúlveda

Int. J. Mol. Sci. 2023, 24(7), 6467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076467 - 30 Mar 2023

Cited by 3 | Viewed by 1872

Abstract

Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor [...] Read more.

Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-β1) expression and extracellular matrix deposition. Small extracellular vesicles (SEVs) from mesenchymal stromal cells (MSCs) are being investigated to treat myocardial infarction, using different strategies to bolster their therapeutic ability. Here, we generated TERT-immortalized human MSC cell lines (MSC-T) engineered to overexpress two forms of cleavage-resistant OSM fused to CD81TM (OSM-SEVs), which allows the display of the cytokine at the surface of secreted SEVs. The therapeutic potential of OSM-SEVs was assessed in vitro using human cardiac ventricular fibroblasts (HCF-Vs) activated by TGF-β1. Compared with control SEVs, OSM-loaded SEVs reduced proliferation in HCF-V and blunted telo-collagen expression. When injected intraperitoneally into mice treated with isoproterenol, OSM-loaded SEVs reduced fibrosis, prevented cardiac hypertrophy, and increased angiogenesis. Overall, we demonstrate that the enrichment of functional OSM on the surface of MSC-T-SEVs increases their potency in terms of anti-fibrotic and pro-angiogenic properties, which opens new perspectives for this novel biological product in cell-free-based therapies. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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16 pages, 3706 KiB

Open AccessArticle

Mitochondrial Metabolism and EV Cargo of Endothelial Cells Is Affected in Presence of EVs Derived from MSCs on Which HIF Is Activated

by Federica Zanotti, Ilaria Zanolla, Martina Trentini, Elena Tiengo, Tommaso Pusceddu, Danilo Licastro, Margherita Degasperi, Sara Leo, Elena Tremoli, Letizia Ferroni and Barbara Zavan

Int. J. Mol. Sci. 2023, 24(6), 6002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24066002 - 22 Mar 2023

Cited by 6 | Viewed by 1647

Abstract

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have attracted growing interest as a possible novel therapeutic agent for the management of different cardiovascular diseases (CVDs). Hypoxia significantly enhances the secretion of angiogenic mediators from MSCs as well as sEVs. The [...] Read more.

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have attracted growing interest as a possible novel therapeutic agent for the management of different cardiovascular diseases (CVDs). Hypoxia significantly enhances the secretion of angiogenic mediators from MSCs as well as sEVs. The iron-chelating deferoxamine mesylate (DFO) is a stabilizer of hypoxia-inducible factor 1 and consequently used as a substitute for environmental hypoxia. The improved regenerative potential of DFO-treated MSCs has been attributed to the increased release of angiogenic factors, but whether this effect is also mediated by the secreted sEVs has not yet been investigated. In this study, we treated adipose-derived stem cells (ASCs) with a nontoxic dose of DFO to harvest sEVs (DFO-sEVs). Human umbilical vein endothelial cells (HUVECs) treated with DFO-sEVs underwent mRNA sequencing and miRNA profiling of sEV cargo (HUVEC-sEVs). The transcriptomes revealed the upregulation of mitochondrial genes linked to oxidative phosphorylation. Functional enrichment analysis on miRNAs of HUVEC-sEVs showed a connection with the signaling pathways of cell proliferation and angiogenesis. In conclusion, mesenchymal cells treated with DFO release sEVs that induce in the recipient endothelial cells molecular pathways and biological processes strongly linked to proliferation and angiogenesis. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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17 pages, 4732 KiB

Open AccessArticle

Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1⁺CD31⁻ Cells

by Shiming Pu, Qian Wang, Qin Liu, Hongxia Zhao, Zuping Zhou and Qiong Wu

Int. J. Mol. Sci. 2022, 23(20), 12455; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012455 - 18 Oct 2022

Cited by 2 | Viewed by 2952

Abstract

Aim: Sca-1⁺CD31⁻ cells are resident cardiac progenitor cells, found in many mammalian tissues including the heart, and able to differentiate into cardiomyocytes in vitro and in vivo. Our previous work indicated that heart-derived Sca-1⁺CD31⁻ cells increased the [...] Read more.

Aim: Sca-1⁺CD31⁻ cells are resident cardiac progenitor cells, found in many mammalian tissues including the heart, and able to differentiate into cardiomyocytes in vitro and in vivo. Our previous work indicated that heart-derived Sca-1⁺CD31⁻ cells increased the Nr1d1 mRNA level of Nr1d1 with aging. However, how Nr1d1 affects the senescence of Sca-1⁺CD31⁻ cells. Methods: Overexpression and knockdown of Nr1d1 in Sca-1⁺CD31⁻ cells and mouse cardiac myocyte (MCM) cell lines were performed by lentiviral transduction. The effects of Nr1d1 abundance on cell differentiation, proliferation, apoptosis, cell cycle, and transcriptomics were evaluated. Moreover, binding of Nr1d1 to the promoter region of Nr4a3 and Serpina3 was examined by a luciferase reporter assay. Results and Conclusions: Upregulation Nr1d1 in young Sca-1⁺CD31⁻ cells inhibited cell proliferation and promoted apoptosis. However, depletion of Nr1d1 in aged Sca-1⁺CD31⁻ cells promoted cell proliferation and inhibited apoptosis. Furthermore, Nr1d1 was negatively associated with cell proliferation, promoting apoptosis and senescence-associated beta-galactosidase production in MCMs. Our findings show that Nr1d1 stimulates Serpina3 expression through its interaction with Nr4a3. Nr1d1 may therefore act as a potent anti-aging receptor that can be a therapeutic target for aging-related diseases. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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15 pages, 4207 KiB

Open AccessArticle

The Effects of Hypoxic Preconditioned Murine Mesenchymal Stem Cells on Post-Infarct Arrhythmias in the Mouse Model

by Beschan Ahmad, Anna Skorska, Markus Wolfien, Haval Sadraddin, Heiko Lemcke, Praveen Vasudevan, Olaf Wolkenhauer, Gustav Steinhoff, Robert David and Ralf Gaebel

Int. J. Mol. Sci. 2022, 23(16), 8843; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168843 - 09 Aug 2022

Cited by 3 | Viewed by 1442

Abstract

Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells [...] Read more.

Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells (MSC) showed their potential in MI therapy. Our study aimed to investigate the effects of MSC injection on post-infarction arrhythmia. We used our murine double infarction model, which we previously established, to more closely mimic the clinical situation and intramyocardially injected hypoxic pre-conditioned murine MSC to the infarction border. Thereafter, various types of arrhythmias were recorded and analyzed. We observed a homogenous distribution of all types of arrhythmias after the first infarction, without any significant differences between the groups. Yet, MSC therapy after double infarction led to a highly significant reduction in simple and complex arrhythmias. Moreover, RNA-sequencing of samples from stem cell treated mice after re-infarction demonstrated a significant decline in most arrhythmias with reduced inflammatory pathways. Additionally, following stem-cell therapy we found numerous highly expressed genes to be either linked to lowering the risk of heart failure, cardiomyopathy or sudden cardiac death. Moreover, genes known to be associated with arrhythmogenesis and key mutations underlying arrhythmias were downregulated. In summary, our stem-cell therapy led to a reduction in cardiac arrhythmias after MI and showed a downregulation of already established inflammatory pathways. Furthermore, our study reveals gene regulation pathways that have a potentially direct influence on arrhythmogenesis after myocardial infarction. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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Review

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17 pages, 4423 KiB

Open AccessReview

New Approaches in Heart Research: Prevention Instead of Cardiomyoplasty?

by Ralf Gaebel, Cajetan Lang, Praveen Vasudevan, Larissa Lührs, Katherine Athayde Teixeira de Carvalho, Eltyeb Abdelwahid and Robert David

Int. J. Mol. Sci. 2023, 24(10), 9017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109017 - 19 May 2023

Cited by 1 | Viewed by 1555

Abstract

Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery [...] Read more.

Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery disease is mainly the result of chronic disorders such as high blood pressure, diabetes, and dyslipidemia. In the modern obesogenic environment, many people are at greater risk of being overweight or obese. The hemodynamic load on the heart is influenced by extreme obesity, which often leads to myocardial infarction (MI), cardiac arrhythmias, and heart failure. In addition, obesity leads to a chronic inflammatory state and negatively affects the wound-healing process. It has been known for many years that lifestyle interventions such as exercise, healthy nutrition, and smoking cessation drastically reduce cardiovascular risk and have a preventive effect against disorders in the healing process. However, little is known about the underlying mechanisms, and there is significantly less high-quality evidence compared to pharmacological intervention studies. Due to the immense potential of prevention in heart research, the cardiologic societies are calling for research work to be intensified, from basic understanding to clinical application. The topicality and high relevance of this research area are also evident from the fact that in March 2018, a one-week conference on this topic with contributions from top international scientists took place as part of the renowned “Keystone Symposia” (“New Insights into the Biology of Exercise”). Consistent with the link between obesity, exercise, and cardiovascular disease, this review attempts to draw lessons from stem-cell transplantation and preventive exercise. The application of state-of-the-art techniques for transcriptome analysis has opened new avenues for tailoring targeted interventions to very individual risk factors. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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14 pages, 849 KiB

Open AccessReview

Modified mRNA as a Treatment for Myocardial Infarction

by Yu Wang, Meiping Wu and Haidong Guo

Int. J. Mol. Sci. 2023, 24(5), 4737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054737 - 01 Mar 2023

Cited by 3 | Viewed by 3613

Abstract

Myocardial infarction (MI) is a severe disease with high mortality worldwide. However, regenerative approaches remain limited and with poor efficacy. The major difficulty during MI is the substantial loss of cardiomyocytes (CMs) with limited capacity to regenerate. As a result, for decades, researchers [...] Read more.

Myocardial infarction (MI) is a severe disease with high mortality worldwide. However, regenerative approaches remain limited and with poor efficacy. The major difficulty during MI is the substantial loss of cardiomyocytes (CMs) with limited capacity to regenerate. As a result, for decades, researchers have been engaged in developing useful therapies for myocardial regeneration. Gene therapy is an emerging approach for promoting myocardial regeneration. Modified mRNA (modRNA) is a highly potential delivery vector for gene transfer with its properties of efficiency, non-immunogenicity, transiency, and relative safety. Here, we discuss the optimization of modRNA-based therapy, including gene modification and delivery vectors of modRNA. Moreover, the effective of modRNA in animal MI treatment is also discussed. We conclude that modRNA-based therapy with appropriate therapeutical genes can potentially treat MI by directly promoting proliferation and differentiation, inhibiting apoptosis of CMs, as well as enhancing paracrine effects in terms of promoting angiogenesis and inhibiting fibrosis in heart milieu. Finally, we summarize the current challenges of modRNA-based cardiac treatment and look forward to the future direction of such treatment for MI. Further advanced clinical trials incorporating more MI patients should be conducted in order for modRNA therapy to become practical and feasible in real-world treatment. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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21 pages, 1038 KiB

Open AccessReview

The Role of Blood-Derived Factors in Protection and Regeneration of Aged Tissues

by Anna L. Höving, Kazuko E. Schmidt, Barbara Kaltschmidt, Christian Kaltschmidt and Cornelius Knabbe

Int. J. Mol. Sci. 2022, 23(17), 9626; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179626 - 25 Aug 2022

Cited by 4 | Viewed by 1980

Abstract

Tissue regeneration substantially relies on the functionality of tissue-resident endogenous adult stem cell populations. However, during aging, a progressive decline in organ function and regenerative capacities impedes endogenous repair processes. Especially the adult human heart is considered as an organ with generally low [...] Read more.

Tissue regeneration substantially relies on the functionality of tissue-resident endogenous adult stem cell populations. However, during aging, a progressive decline in organ function and regenerative capacities impedes endogenous repair processes. Especially the adult human heart is considered as an organ with generally low regenerative capacities. Interestingly, beneficial effects of systemic factors carried by young blood have been described in diverse organs including the heart, brain and skeletal muscle of the murine system. Thus, the interest in young blood or blood components as potential therapeutic agents to target age-associated malignancies led to a wide range of preclinical and clinical research. However, the translation of promising results from the murine to the human system remains difficult. Likewise, the establishment of adequate cellular models could help to study the effects of human blood plasma on the regeneration of human tissues and particularly the heart. Facing this challenge, this review describes the current knowledge of blood plasma-mediated protection and regeneration of aging tissues. The current status of preclinical and clinical research examining blood borne factors that act in stem cell-based tissue maintenance and regeneration is summarized. Further, examples of cellular model systems for a more detailed examination of selected regulatory pathways are presented. Full article

(This article belongs to the Special Issue Molecular Research on Heart Protection)

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