338 results found
Squiers GT, McLellan MA, Ilinykh A, et al., 2021, Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: 2252-2261, ISSN: 0008-6363
Plikus M, Wang X, Sinha S, et al., 2021, Fibroblasts: Origins, definitions, and functions in health and disease, CELL, Vol: 184, Pages: 3852-3872, ISSN: 0092-8674
Harrison DE, Strong R, Reifsnyder P, et al., 2021, 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex., Aging Cell, Vol: 20
In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
Debuque RJ, Nowoshilow S, Chan KE, et al., 2021, Distinct toll-like receptor signaling in the salamander response to tissue damage., Dev Dyn
BACKGROUND: Efficient wound healing or pathogen clearance both rely on balanced inflammatory responses. Inflammation is essential for effective innate immune-cell recruitment; however, excessive inflammation will result in local tissue destruction, pathogen egress, and ineffective pathogen clearance. Sterile and nonsterile inflammation operate with competing functional priorities but share common receptors and overlapping signal transduction pathways. In regenerative organisms such as the salamander, whole limbs can be replaced after amputation while exposed to a nonsterile environment. In mammals, exposure to sterile-injury Damage Associated Molecular Patterns (DAMPS) alters innate immune-cell responsiveness to secondary Pathogen Associated Molecular Pattern (PAMP) exposure. RESULTS: Using new phospho-flow cytometry techniques to measure signaling in individual cell subsets we compared mouse to salamander inflammation. These studies demonstrated evolutionarily conserved responses to PAMP ligands through toll-like receptors (TLRs) but identified key differences in response to DAMP ligands. Co-exposure of macrophages to DAMPs/PAMPs suppressed MAPK signaling in mammals, but not salamanders, which activate sustained MAPK stimulation in the presence of endogenous DAMPS. CONCLUSIONS: These results reveal an alternative signal transduction network compatible with regeneration that may ultimately lead to the promotion of enhanced tissue repair in mammals.
Kuraitis D, Rosenthal N, Boh E, et al., 2021, Macrophages in dermatology: pathogenic roles and targeted therapeutics, ARCHIVES OF DERMATOLOGICAL RESEARCH, ISSN: 0340-3696
Forte E, McLellan MA, Skelly DA, et al., 2021, Ex uno, plures-From One Tissue to Many Cells: A Review of Single-Cell Transcriptomics in Cardiovascular Biology, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22
Tombor LS, John D, Glaser SF, et al., 2021, Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Forte E, Perkins B, Sintou A, et al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322
Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.
Yucel N, Chang AC, Day JW, et al., 2020, Author Correction: Humanizing the mdx mouse model of DMD: the long and the short of it (npj Regenerative Medicine, (2018), 3, 1, (4), 10.1038/s41536-018-0045-4), npj Regenerative Medicine, Vol: 5
The original version of the published Article contained an error in the initial cross depicted in Fig. 2. The initial cross should be a male mTRHet heterozygous animal crossed with a female mdx4cv/4cv homozygous animal. This has been corrected in the HTML and PDF version of the Article.
Miller RA, Harrison DE, Allison DB, et al., 2020, Canagliflozin extends life span in genetically heterogeneous male but not female mice, JCI INSIGHT, Vol: 5
McLellan MA, Skelly DA, Dona MSI, et al., 2020, High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy, Circulation, Vol: 142, Pages: 1448-1463, ISSN: 0009-7322
BACKGROUND: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. METHODS: We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. RESULTS: Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast-Cilp and Fibroblast-Thbs4, emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast-Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. CONCLUSIONS: These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, high
Forte E, Daigle S, Rosenthal NA, 2020, Protocol for Isolation of Cardiac Interstitial Cells from Adult Murine Hearts for Unbiased Single Cell Profiling., STAR Protoc, Vol: 1
Interstitial cells have a crucial role in cardiac fibrosis and repair of the mammalian heart. Single-cell profiling using droplet-based technology has revolutionized the investigation of cell states and identities. Here, we present a protocol for the efficient isolation of high-quality live nucleated non-cardiomyocytes from adult murine heart, for unbiased single-cell RNA sequencing using 10× Chromium technology. This protocol has been applied to homeostatic and injured hearts from different mouse strains. For complete details on the use and execution of this protocol, please refer to Forte et al. (2020).
Sattler S, Baxan N, Ng FS, et al., 2020, Myocardial damage induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol-hydrochloride isused for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis.To assess if isoproterenol-induced cardiomyocyte necrosistriggersan adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of 160mg/kg isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum, as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Sintou A, Mansfield C, Iacob A-O, et al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X
Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.
Bouvet M, Claude O, Roux M, et al., 2020, Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells., Scientific Reports, Vol: 10, Pages: 11404-11404, ISSN: 2045-2322
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.
Epstein JA, Rosenthal N, Feldman AM, 2020, Teasing the immune system to repair the heart, New England Journal of Medicine, Vol: 382, Pages: 1660-1662, ISSN: 0028-4793
Ferrini A, Skaalure S, Furtado MB, et al., 2020, 4D ECHOCARDIOGRAPHY AND MYOCARDIAL MECHANICS ASSESSMENT FOLLOWING INJECTION OF A THERMORESPONSIVE HYDROGEL FOR HEART FAILURE TREATMENT, Publisher: SPRINGER, Pages: 282-282
Forte E, Skelly DA, Chen M, et al., 2020, Dynamic interstitial cell response during myocardial infarction predicts resilience to rupture in genetically diverse mice, Cell Reports, Vol: 30, Pages: 3149-3163.e6, ISSN: 2211-1247
Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation of a scar whose structural characteristics dictate propensity to favorable healing or detrimental cardiac wall rupture. To elucidate the cellular processes underlying scar formation, here we perform unbiased single-cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardial-derived cells. Sixteen interstitial cell clusters are revealed, five of which were of epicardial origin. Focusing on stromal cells, we define 11 sub-clusters, including diverse cell states of epicardial- and endocardial-derived fibroblasts. Comparing transcript profiles from post-infarction hearts in C57BL/6J and 129S1/SvImJ inbred mice, which displays a marked divergence in the frequency of cardiac rupture, uncovers an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mouse hearts, defining a crucial time window of pathological remodeling that predicts disease outcome.
Sattler S, Baxan N, Chowdhury R, et al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac MRI, Disease Models & Mechanisms, Vol: 12, Pages: 1-10, ISSN: 1754-8403
Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the TLR-7 agonist Resiquimod induces auto-antibodies and systemic tissue damage including in the heart, and is used as an inducible mouse model of Systemic Lupus Erythematosus (SLE).Here, we show that over-activation of the TLR-7 pathway of viral recognition by Resiquimod-treatment of CFN mice induces severe thrombocytopenia and internal bleeding which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results to ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed a detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes.In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis will improve interpretation of disease mechanisms and diagnostic sensitivity.
Ascenzi F, Barberi L, Dobrowolny G, et al., 2019, Effects of IGF-1 isoforms on muscle growth and sarcopenia, Aging Cell, Vol: 18, ISSN: 1474-9718
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin‐like growth factor‐1 (IGF‐1) has been implicated in many anabolic pathways in skeletal muscle. IGF‐1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF‐1Ea and IGF‐1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF‐1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF‐1Ea or IGF‐1Eb transgenes was protective against age‐related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1‐α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF‐1Ea and MLC/IGF‐1Eb mice during aging. These data suggest that IGF‐1 is a promising therapeutic agent in staving off advancing muscle weakness.
Ferrini A, Stevens MM, Sattler S, et al., 2019, Toward regeneration of the heart: Bioengineering strategies for immunomodulation, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.
Sintou A, Rifai SE, Mansfield C, et al., 2019, Persistent anti-heart autoimmunity causes cardiomyocyte damage in chronic heart failure, Publisher: bioRxiv
Although clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF). Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy. These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.
Salimova E, Nowak KJ, Estrada AC, et al., 2019, Variable outcomes of human heart attack recapitulated in genetically diverse mice, npj Regenerative Medicine, Vol: 4, Pages: 1-15, ISSN: 2057-3995
Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction.
Wilmanns JC, Pandey R, Hon O, et al., 2019, Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease, Molecular Metabolism, Vol: 20, Pages: 102-114, ISSN: 2212-8778
OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown. METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model. RESULTS: ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice. CONCLUSIONS: This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise
Brito L, Mylonaki I, Moroz E, et al., 2019, Epicardial cell transfection with cationic polymeric nanocomplexes, British-Society-for-Gene-and-Cell-Therapy Autumn Conference, Publisher: MARY ANN LIEBERT, INC, Pages: A9-A9, ISSN: 1043-0342
Paracrine signalling has been shown to contribute to heart regeneration after myocardial infarction (MI). As an important signalling regulatory centre, the epicardium is crucial for the heart development. Moreover, it is re-activated after MI, indicating its involvement in the response to this injury. This project aims to accomplish in situ transfection of the epicardium to stimulate the regenerative signalling pathways after MI.Here an in vitro proof of concept of epicardial cell transfection with nanocomplexes is presented. pABOL polyplexes, resulting from complexation of a bioreducible polymer with a GFP gene plasmid (pCAG-GFP), were able to transfect epicardial cells when added in suspension to the culture. The pCAG-GFP-pABOL polyplexes formulation was the most suitable when compared to Lipofectamine, Fugene or naked plasmid, revealing 45.9±9.7% of cell viability and 39.4±6.4% of transfection efficiency. Moreover, the freeze-drying of the pABOL polyplexes was tested. pABOL polyplexes formed in water and in the different sugar/surfactants HEPES buffers. The ζ-potential of these polyplexes ranged between +20 and +30mV. After the freeze-drying, pABOL polyplexes only maintained their transfection activity when formed in sugar-containing buffers.These preliminary results indicate for the first time the advantage of using pABOL polymer in comparison with standard transfection reagents for epicardial cells transfection and the possibility of retaining transfection activity of pABOL polyplexes when freeze-dried. Our final aim is to use nanoneedles, which can transfer substances to the epicardial layer alone, to deliver these polyplexes.
Rosenthal N, Kress M, Gruss P, et al., 2019, BK Viral enhancer element and a human cellular homolog, Biotechnology and Biological Frontiers, Pages: 351-364, ISBN: 9780367020460
Identification of elements that control the initiation of transcription is a crucial step in understanding the regulation of eukaryotic gene expression. Approaches to the problem of transcriptional control with animal viruses as a model system have recently uncovered transcriptional regulatory elements, called enhancers. This chapter utilizes the human papovavirus BKV as a viral model of eukaryotic transcriptional control. The 68-bp BKV triplication functions as an enhancer element for gene expression in a number of cell types without a pronounced host cell preference. To investigate the possibility that viral enhancers may have cellular homologs, we screened a human genomic λ library for sequences related to the BKV tandem triplication with the 216-bp BKV Hae III fragment as a probe. The sequence length and arrangement of the human genomic tandem repeats is different from that of the BKV enhancer, certain similarities such as the core region and the glycoprotein-rich hexanucleotides are impressive.
Lavine KJ, Pinto AR, Epelman S, et al., 2018, The macrophage in cardiac homeostasis and disease JACC macrophage in CVD series (Part 4), Journal of the American College of Cardiology, Vol: 72, Pages: 2213-2230, ISSN: 0735-1097
Macrophages are integral components of cardiac tissue and exert profound effects on the healthy and diseased heart. Paradigm shifting studies using advanced molecular techniques have revealed significant complexity within these macrophage populations that reside in the heart. In this final of a 4-part review series covering the macrophage in cardiovascular disease, the authors review the origins, dynamics, cell surface markers, and respective functions of each cardiac macrophage subset identified to date, including in the specific scenarios of myocarditis and after myocardial infarction. Looking ahead, a deeper understanding of the diverse and often dichotomous functions of cardiac macrophages will be essential for the development of targeted therapies to mitigate injury and orchestrate recovery of the diseased heart. Moreover, as macrophages are critical for cardiac healing, they are an emerging focus for therapeutic strategies aimed at minimizing cardiomyocyte death, ameliorating pathological cardiac remodeling, and for treating heart failure and after myocardial infarction.
Forte E, Furtado MB, Rosenthal N, 2018, The interstitium in cardiac repair: role of the immune-stromal cell interplay, Nature Reviews Cardiology, Vol: 15, Pages: 601-616, ISSN: 1759-5002
Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases.
Panahi M, Papanikolaou A, Torabi A, et al., 2018, Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition, Cardiovascular Research, Vol: 114, Pages: 1445-1461, ISSN: 1755-3245
Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.
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