Imperial College London

ProfessorNadiaRosenthal

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiovascular Science&ScientificDirector
 
 
 
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Contact

 

+44 (0)20 7594 2737n.rosenthal

 
 
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Location

 

424W2ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

370 results found

Racine JJ, Bachman JF, Zhang J-G, Misherghi A, Khadour R, Kaisar S, Bedard O, Jenkins C, Abbott A, Forte E, Rainer P, Rosenthal N, Sattler S, Serreze DVet al., 2024, Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy., J Immunol, Vol: 212, Pages: 1287-1306

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.

Journal article

Nunes Santos L, Sousa Costa ÂM, Nikolov M, Carvalho JE, Coelho Sampaio A, Stockdale FE, Wang GF, Andrade Castillo H, Bortoletto Grizante M, Dudczig S, Vasconcelos M, Rosenthal N, Jusuf PR, Nim HT, de Oliveira P, Guimarães de Freitas Matos T, Nikovits W, Tambones IL, Figueira ACM, Schubert M, Ramialison M, Xavier-Neto Jet al., 2024, Unraveling the evolutionary origin of the complex Nuclear Receptor Element (cNRE), a cis-regulatory module required for preferential expression in the atrial chamber., Commun Biol, Vol: 7

Cardiac function requires appropriate proteins in each chamber. Atria requires slow myosin to act as reservoirs, while ventricles demand fast myosin for swift pumping. Myosins are thus under chamber-biased cis-regulation, with myosin gene expression imbalances leading to congenital heart dysfunction. To identify regulatory inputs leading to cardiac chamber-biased expression, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives preferential expression to the atria. We show that SMyHC III gene states are orchestrated by a complex Nuclear Receptor Element (cNRE) of 32 base pairs. Using transgenesis in zebrafish and mice, we demonstrate that preferential atrial expression is achieved by a combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Using comparative genomics, we show that the cNRE might have emerged from an endogenous viral element through infection of an ancestral host germline, revealing an evolutionary pathway to cardiac chamber-specific expression.

Journal article

Bengel F, Epstein JA, Gropler R, Haberkorn U, Kramann R, Lavine K, Leuschner F, Liu Y, Rosenthal N, Wu Het al., 2024, Linking immune modulation to cardiac fibrosis, Nature Cardiovascular Research, Vol: 3, Pages: 414-419

On 21–23 September 2023, the Immuno-Cardiology Symposium was hosted by the Leducq Foundation Networks of Excellence Program (The Inflammatory-Fibrosis Axis in Adverse LV Remodeling: translating mechanisms into new diagnostics and therapeutics) at The Jackson Laboratory in Bar Harbor, Maine. The symposium highlighted recent advances in the basic science of dysregulated immune system activation and fibrosis in response to cardiac injury.

Journal article

Dumont BL, Gatti DM, Ballinger MA, Lin D, Phifer-Rixey M, Sheehan MJ, Suzuki TA, Wooldridge LK, Frempong HO, Lawal RA, Churchill GA, Lutz C, Rosenthal N, White JK, Nachman MWet al., 2024, Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models., PLoS Genet, Vol: 20

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently developed, sequenced, and phenotyped a set of 11 inbred strains derived from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from one of five environmentally distinct locations across North and South America. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the GRCm39 mouse reference, with 42.5% of variants in the Nachman strain genomes absent from current classical inbred mouse strain panels. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels. These novel wild-derived inbred mouse strain resources are set to empower new discoveries in both basic and preclinical research.

Journal article

Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, Flurkey K, Ginsburg BC, Murrell MD, Javors MA, Lopez-Cruzan M, Nelson JF, Willcox BJ, Allsopp R, Watumull DM, Watumull DG, Cortopassi G, Kirkland JL, Tchkonia T, Choi YG, Yousefzadeh MJ, Robbins PD, Mitchell JR, Acar M, Sarnoski EA, Bene MR, Salmon A, Kumar N, Miller RAet al., 2024, Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used., Geroscience, Vol: 46, Pages: 795-816

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.

Journal article

Racine JJ, Misherghi A, Dwyer JR, Maser R, Forte E, Bedard O, Sattler S, Pugliese A, Landry L, Elso C, Nakayama M, Mannering S, Rosenthal N, Serreze DVet al., 2023, HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice., J Immunol, Vol: 211, Pages: 1792-1805

In an effort to improve HLA-"humanized" mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining β2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8-restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived β cell autoantigen-specific TCRs.

Journal article

Robertson SJ, Bedard O, McNally KL, Shaia C, Clancy CS, Lewis M, Broeckel RM, Chiramel AI, Shannon JG, Sturdevant GL, Rosenke R, Anzick SL, Forte E, Preuss C, Baker CN, Harder JM, Brunton C, Munger S, Bruno DP, Lack JB, Leung JM, Shamsaddini A, Gardina P, Sturdevant DE, Sun J, Martens C, Holland SM, Rosenthal NA, Best SMet al., 2023, Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19, NATURE COMMUNICATIONS, Vol: 14

Journal article

Chella Krishnan K, El Hachem E-J, Keller MP, Patel SG, Carroll L, Vegas AD, Gerdes Gyuricza I, Light C, Cao Y, Pan C, Kaczor-Urbanowicz KE, Shravah V, Anum D, Pellegrini M, Lee CF, Seldin MM, Rosenthal NA, Churchill GA, Attie AD, Parker B, James DE, Lusis AJet al., 2023, Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy., Elife, Vol: 12

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Journal article

Snyder JM, Casey KM, Galecki A, Harrison DE, Jayarathne H, Kumar N, Macchiarini F, Rosenthal N, Sadagurski M, Salmon AB, Strong R, Miller RA, Ladiges Wet al., 2023, Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice, GEROSCIENCE, Vol: 45, Pages: 385-397, ISSN: 2509-2715

Journal article

Strong R, Miller RA, Cheng CJ, Nelson JF, Gelfond J, Allani SK, Diaz V, Dorigatti AO, Dorigatti J, Fernandez E, Galecki A, Ginsburg B, Hamilton KL, Javors MA, Kornfeld K, Kaeberlein M, Kumar S, Lombard DB, Lopez-Cruzan M, Miller BF, Rabinovitch P, Reifsnyder P, Rosenthal NA, Bogue MA, Salmon AB, Suh Y, Verdin E, Weissbach H, Newman J, Maccchiarini F, Harrison DEet al., 2022, Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice., Aging Cell, Vol: 21

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.

Journal article

Svenson KL, Krasinski SD, Ellis M, Rosenthal N, Liu ET, Fasman KHet al., 2022, Animals, quality and the pursuit of relevance, DISEASE MODELS & MECHANISMS, Vol: 15, ISSN: 1754-8403

Journal article

Debuque RJ, Nowoshilow S, Chan KE, Rosenthal NA, Godwin JWet al., 2022, Distinct toll-like receptor signaling in the salamander response to tissue damage, DEVELOPMENTAL DYNAMICS, Vol: 251, Pages: 988-1003, ISSN: 1058-8388

Journal article

Auchampach J, Han L, Huang GN, Kuhn B, Lough JW, O'Meara CC, Payumo AY, Rosenthal NA, Sucov HM, Yutzey KE, Patterson Met al., 2022, Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 322, Pages: H579-H596, ISSN: 0363-6135

Journal article

Squiers GT, McLellan MA, Ilinykh A, Branca J, Rosenthal NA, Pinto ARet al., 2022, Corrigendum to: Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones., Cardiovasc Res, Vol: 118

Journal article

Forte E, Ramialison M, Nim HT, Mara M, Li JY, Cohn R, Daigle SL, Boyd S, Stanley EG, Elefanty AG, Hinson JT, Costa MW, Rosenthal NA, Furtado MBet al., 2022, Adult mouse fibroblasts retain organ-specific transcriptomic identity, ELIFE, Vol: 11, ISSN: 2050-084X

Journal article

Kuraitis D, Rosenthal N, Boh E, McBurney Eet al., 2022, Macrophages in dermatology: pathogenic roles and targeted therapeutics, ARCHIVES OF DERMATOLOGICAL RESEARCH, Vol: 314, Pages: 133-140, ISSN: 0340-3696

Journal article

Mohenska M, Tan NM, Tokolyi A, Furtado MB, Costa MW, Perry AJ, Hatwell-Humble J, van Duijvenboden K, Nim HT, Ji YMM, Charitakis N, Bienroth D, Bolk F, Vivien C, Knaupp AS, Powell DR, Elliott DA, Porrello ER, Nilsson SK, del Monte-Nieto G, Rosenthal NA, Rossello FJ, Polo JM, Ramialison Met al., 2022, 3D-cardiomics: A spatial transcriptional atlas of the mammalian heart, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 163, Pages: 20-32, ISSN: 0022-2828

Journal article

Brito L, Mylonaki I, Grigsby CL, Seong H, Higgins SG, Smart N, Noseda M, Rosenthal N, Harding S, Stevens Met al., 2021, Genetic Enhancement of Epicardial Paracrine Signalling for Cardiac Regeneration, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Debuque RJ, Hart AJ, Johnson GH, Rosenthal NA, Godwin JWet al., 2021, Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration, FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, Vol: 9, ISSN: 2296-634X

Journal article

Squiers GT, McLellan MA, Ilinykh A, Branca J, Rosenthal NA, Pinto ARet 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

Journal article

Plikus M, Wang X, Sinha S, Forte E, Thompson SM, Herzog EL, Driskell RR, Rosenthal N, Biernaskie J, Horsley Vet al., 2021, Fibroblasts: Origins, definitions, and functions in health and disease, CELL, Vol: 184, Pages: 3852-3872, ISSN: 0092-8674

Journal article

Harrison DE, Strong R, Reifsnyder P, Kumar N, Fernandez E, Flurkey K, Javors MA, Lopez-Cruzan M, Macchiarini F, Nelson JF, Markewych A, Bitto A, Sindler AL, Cortopassi G, Kavanagh K, Leng L, Bucala R, Rosenthal N, Salmon A, Stearns TM, Bogue M, Miller RAet 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, ISSN: 1474-9718

Journal article

Forte E, McLellan MA, Skelly DA, Rosenthal NAet al., 2021, <i>Ex uno, plures</i>-From One Tissue to Many Cells: A Review of Single-Cell Transcriptomics in Cardiovascular Biology, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22

Journal article

Tombor LS, John D, Glaser SF, Luxan G, Forte E, Furtado M, Rosenthal N, Baumgarten N, Schulz MH, Wittig J, Rogg E-M, Manavski Y, Fischer A, Muhly-Reinholz M, Klee K, Looso M, Selignow C, Acker T, Bibli S-I, Fleming I, Patrick R, Harvey RP, Abplanalp WT, Dimmeler Set al., 2021, Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction, NATURE COMMUNICATIONS, Vol: 12

Journal article

Macchiarini F, Miller RA, Strong R, Rosenthal N, Harrison DEet al., 2021, NIA Interventions Testing Program: A collaborative approach for investigating interventions to promote healthy aging, Handbook of the Biology of Aging, Pages: 219-235, ISBN: 9780128159620

The NIA Interventions Testing Program (ITP) investigates the potential of dietary interventions to promote healthy aging and provides preliminary data on cellular mechanisms and pathways that affect aging. Members of the research community propose compounds for study, and lifespan and health studies are performed at three sites to demonstrate the degree of reproducibility. A genetically heterogeneous mouse model is used to reduce the influence of strain-specific characteristics on the outcomes, and sufficient mice are used to detect a 10% change in mean lifespan with 80% power if at least two sites contribute data. There have been several positive findings that have prompted additional studies within the ITP and from the broader research community, including data on rapamycin, acarbose, 17α-estradiol, nordihydroguaiaretic acid, Protandim, and glycine. This chapter describes the ITP structure, summarizes findings to date and how they have led to additional studies, and discusses the future role of the ITP in promoting research on antiaging interventions.

Book chapter

Forte E, Panahi M, Baxan N, Ng FS, Boyle JJ, Branca J, Bedard O, Hasham MG, Benson L, Harding SE, Rosenthal N, Sattler Set 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.

Journal article

Yucel N, Chang AC, Day JW, Rosenthal N, Blau HMet al., 2020, Humanizing the mdx mouse model of DMD: the long and the short of it (vol 3, 4, 2018), NPJ REGENERATIVE MEDICINE, Vol: 5

Journal article

Forte E, Perkins B, Sintou A, Kallkat HS, Papanikolaou A, Jenkins C, Alsubaie M, Chowdhury RA, Duffy TM, Skelly DA, Branca J, Bellahcene M, Schneider M, Harding S, Furtado MB, Ng FS, Hasham MG, Rosenthal N, Sattler Set 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.

Journal article

Miller RA, Harrison DE, Allison DB, Bogue M, Debarba L, Diaz V, Fernandez E, Galecki A, Garvey WT, Jayarathne H, Kumar N, Javors MA, Ladiges WC, Macchiarini F, Nelson J, Reifsnyder P, Rosenthal NA, Sadagurski M, Salmon AB, Smith DL, Snyder JM, Lombard DB, Strong Ret al., 2020, Canagliflozin extends life span in genetically heterogeneous male but not female mice, JCI INSIGHT, Vol: 5

Journal article

McLellan MA, Skelly DA, Dona MSI, Squiers GT, Farrugia GE, Gaynor TL, Cohen CD, Pandey R, Diep H, Vinh A, Rosenthal NA, Pinto ARet 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

Journal article

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