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1.
Immunity ; 56(4): 783-796.e7, 2023 04 11.
Article in English | MEDLINE | ID: mdl-36827982

ABSTRACT

Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear. Here, we identified a fasting-induced switch in leukocyte migration that prolongs monocyte lifespan and alters susceptibility to disease in mice. We show that fasting during the active phase induced the rapid return of monocytes from the blood to the bone marrow. Monocyte re-entry was orchestrated by hypothalamic-pituitary-adrenal (HPA) axis-dependent release of corticosterone, which augmented the CXCR4 chemokine receptor. Although the marrow is a safe haven for monocytes during nutrient scarcity, re-feeding prompted mobilization culminating in monocytosis of chronologically older and transcriptionally distinct monocytes. These shifts altered response to infection. Our study shows that diet-in particular, a diet's temporal dynamic balance-modulates monocyte lifespan with consequences for adaptation to external stressors.


Subject(s)
Bone Marrow , Monocytes , Mice , Animals , Bone Marrow Cells , Fasting , Chemokines/metabolism
2.
Immunity ; 56(7): 1502-1514.e8, 2023 07 11.
Article in English | MEDLINE | ID: mdl-37160117

ABSTRACT

Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.


Subject(s)
Multiple Sclerosis , Animals , Humans , Mice , Central Nervous System , Interleukin-3 , Microglia , Neuroglia/metabolism
3.
Immunity ; 51(5): 899-914.e7, 2019 11 19.
Article in English | MEDLINE | ID: mdl-31732166

ABSTRACT

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.


Subject(s)
Disease Susceptibility , Macrophages/immunology , Macrophages/metabolism , Animals , Biomarkers , Cell Count , Disease Susceptibility/immunology , ErbB Receptors/metabolism , Gene Expression Profiling , Gene Expression Regulation , Gene Regulatory Networks , Ischemia/etiology , Ischemia/metabolism , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Mice , Muscle Cells/immunology , Muscle Cells/metabolism , Myocardial Infarction/etiology , Myocardial Infarction/metabolism , Organ Specificity/genetics , Organ Specificity/immunology , Pneumonia/etiology , Pneumonia/metabolism , Pneumonia/pathology
4.
Nature ; 595(7869): 701-706, 2021 07.
Article in English | MEDLINE | ID: mdl-34262178

ABSTRACT

Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of ß-amyloid (Aß) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aß deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aß and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.


Subject(s)
Alzheimer Disease/metabolism , Astrocytes/physiology , Interleukin-3/metabolism , Microglia/physiology , Animals , Cell Communication , Cells, Cultured , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Stem Cells/physiology
5.
Circ Res ; 133(10): 861-876, 2023 10 27.
Article in English | MEDLINE | ID: mdl-37818671

ABSTRACT

BACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.


Subject(s)
Ferroptosis , Myocytes, Cardiac , Humans , Myocytes, Cardiac/metabolism , Reperfusion , Ischemia/metabolism , Glutathione/metabolism , Phospholipids/metabolism , Phosphatidylcholines
6.
Nature ; 566(7742): 115-119, 2019 02.
Article in English | MEDLINE | ID: mdl-30700910

ABSTRACT

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways1, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin ß7+ natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin ß7- mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-12, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.


Subject(s)
Cardiovascular Diseases/metabolism , Disease Progression , Intestine, Small/cytology , Intraepithelial Lymphocytes/metabolism , Animals , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Cardiovascular Diseases/genetics , Cardiovascular Diseases/prevention & control , Disease Models, Animal , Eating , Enterocytes/cytology , Enterocytes/metabolism , Female , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Integrin beta Chains/genetics , Integrin beta Chains/metabolism , Male , Metabolic Syndrome/genetics , Metabolic Syndrome/metabolism , Metabolic Syndrome/prevention & control , Mice
7.
Nature ; 566(7744): 383-387, 2019 02.
Article in English | MEDLINE | ID: mdl-30760925

ABSTRACT

Sleep is integral to life1. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease2, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6Chigh monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.


Subject(s)
Atherosclerosis/prevention & control , Hematopoiesis/physiology , Sleep/physiology , Animals , Antigens, Ly/metabolism , Atherosclerosis/metabolism , Atherosclerosis/pathology , Bone Marrow Cells/metabolism , Female , Hematopoiesis/drug effects , Hypothalamic Area, Lateral/metabolism , Macrophage Colony-Stimulating Factor/biosynthesis , Macrophage Colony-Stimulating Factor/deficiency , Macrophage Colony-Stimulating Factor/metabolism , Male , Mice , Monocytes/drug effects , Monocytes/metabolism , Myelopoiesis/drug effects , Neutrophils/metabolism , Orexin Receptors/deficiency , Orexin Receptors/metabolism , Orexins/biosynthesis , Orexins/deficiency , Orexins/metabolism , Orexins/pharmacology , Sleep/drug effects , Sleep Deprivation/metabolism , Sleep Deprivation/physiopathology , Sleep Deprivation/prevention & control
8.
Biochem Biophys Res Commun ; 690: 149272, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37992523

ABSTRACT

Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.


Subject(s)
Myocardial Infarction , Humans , Myocardial Infarction/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Macrophages/metabolism , Inflammation/metabolism , Fibroblasts/metabolism
9.
Int J Mol Sci ; 23(9)2022 May 06.
Article in English | MEDLINE | ID: mdl-35563605

ABSTRACT

Despite recent scientific and technological advances, myocardial infarction (MI) still represents a major global health problem, leading to high morbidity and mortality worldwide. During the post-MI wound healing process, dysregulated immune inflammatory pathways and failure to resolve inflammation are associated with maladaptive left ventricular remodeling, progressive heart failure, and eventually poor outcomes. Given the roles of immune cells in the host response against tissue injury, understanding the involved cellular subsets, sources, and functions is essential for discovering novel therapeutic strategies that preserve the protective immune system and promote optimal healing. This review discusses the cellular effectors and molecular signals across multi-organ systems, which regulate the inflammatory and reparative responses after MI. Additionally, we summarize the recent clinical and preclinical data that propel conceptual revolutions in cardiovascular immunotherapy.


Subject(s)
Myocardial Infarction , Humans , Immune System/metabolism , Inflammation/metabolism , Myocardial Infarction/metabolism , Ventricular Remodeling , Wound Healing
10.
J Mol Cell Cardiol ; 161: 116-129, 2021 12.
Article in English | MEDLINE | ID: mdl-34390730

ABSTRACT

MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear. First, to determine the significance of MITOL in unstressed hearts, we assessed the cellular changes with the reduction of MITOL expression by siRNA in neonatal rat primary ventricular cardiomyocytes (NRVMs). MITOL knockdown in NRVMs induced cell death via ferroptosis, a newly defined non-apoptotic programmed cell death, even under no stress conditions. This phenomenon was observed only in NRVMs, not in other cell types. MITOL knockdown markedly reduced mitochondria-localized GPX4, a key enzyme associated with ferroptosis, promoting accumulation of lipid peroxides in mitochondria. In contrast, the activation of GPX4 in MITOL knockdown cells suppressed lipid peroxidation and cell death. MITOL knockdown reduced the glutathione/oxidized glutathione (GSH/GSSG) ratio that regulated GPX4 expression. Indeed, the administration of GSH or N-acetylcysteine improved the expression of GPX4 and viability in MITOL-knockdown NRVMs. MITOL-knockdown increased the expression of the glutathione-degrading enzyme, ChaC glutathione-specific γ-glutamylcyclotransferase 1 (Chac1). The knockdown of Chac1 restored the GSH/GSSG ratio, GPX4 expression, and viability in MITOL-knockdown NRVMs. Further, in cultured cardiomyocytes stressed with DOX, both MITOL and GPX4 were reduced, whereas forced-expression of MITOL suppressed DOX-induced ferroptosis by maintaining GPX4 content. Additionally, MITOL knockdown worsened vulnerability to DOX, which was almost completely rescued by treatment with ferrostatin-1, a ferroptosis inhibitor. In vivo, cardiac-specific depletion of MITOL did not produce obvious abnormality, but enhanced susceptibility to DOX toxicity. Finally, administration of ferrostatin-1 suppressed exacerbation of DOX-induced myocardial damage in MITOL-knockout hearts. The present study demonstrates that MITOL determines the cell fate of cardiomyocytes via the ferroptosis process and plays a key role in regulating vulnerability to DOX treatment. (288/300).


Subject(s)
Cardiomyopathies/chemically induced , Doxorubicin/pharmacology , Glutathione/metabolism , Mitochondrial Proteins/metabolism , Myocytes, Cardiac/drug effects , Ubiquitin-Protein Ligases/metabolism , Animals , Cardiomyopathies/metabolism , Cardiomyopathies/pathology , Cell Death/drug effects , Cells, Cultured , Doxorubicin/adverse effects , Ferroptosis/drug effects , HEK293 Cells , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/genetics , Myocytes, Cardiac/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Rats , Ubiquitin-Protein Ligases/genetics , gamma-Glutamylcyclotransferase/genetics , gamma-Glutamylcyclotransferase/metabolism
11.
Circ J ; 85(6): 929-938, 2021 05 25.
Article in English | MEDLINE | ID: mdl-33658455

ABSTRACT

BACKGROUND: Timely differentiation of monocytes into M2-like macrophages is important in the cardiac healing process after myocardial infarction (MI), but molecular mechanisms governing M2-like macrophage differentiation at the transcriptional level after MI have not been fully understood.Methods and Results:A time-series microarray analysis of mRNAs and microRNAs in macrophages isolated from the infarcted myocardium was performed to identify the microRNAs involved in regulating the process of differentiation to M2-like macrophages. Correlation analysis revealed 7 microRNAs showing negative correlations with the progression of polarity changes towards M2-like subsets. Next, correlation coefficients for the changes in expression of mRNAs and miRNAs over time were calculated for all combinations. As a result, miR-27a-5p was extracted as a possible regulator of the largest number of genes in the pathway for the M2-like polarization. By selecting mouse mRNAs and human mRNAs possessing target sequences of miR-27a-5p and showing expression patterns inversely correlated with that of miR-27a-5p, 8 potential targets of miR-27a-5p were identified, includingPpm1l. Using the mouse bone marrow-derived macrophages undergoing differentiation into M2-like subsets by interleukin 4 stimulation, we confirmed that miR-27a-5p suppressed M2-related genes by negatively regulatingPpm1lexpression. CONCLUSIONS: Ppm1land miR-27a-5p may be the key molecules regulating M2-like polarization, with miR-27a-5p inhibiting the M2-like polarization through downregulation ofPpm1lexpression.


Subject(s)
MicroRNAs , Myocardial Infarction , Animals , Gene Expression Profiling , Macrophages , Mice , MicroRNAs/genetics , Monocytes , Myocardial Infarction/genetics , RNA, Messenger
12.
Heart Lung Circ ; 30(9): 1406-1413, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33863668

ABSTRACT

BACKGROUND: New-onset atrial tachyarrhythmia (ATA) often develops after atrial septal defect (ASD) closure. Its development raises some potential concerns such as stroke and bleeding complications caused by anticoagulant therapy and limited access to the left atrium for catheter ablation. Although it is essential to identify the risk factors of new-onset ATA, few studies have examined these factors. This study investigated unknown risk factors for the development of new-onset ATA after transcatheter ASD closure in patients without a history of ATA. METHODS: A total of 238 patients without a history of ATA, aged ≥18 years and who underwent transcatheter ASD closure at the current hospital were reviewed. Patient characteristics were compared between the groups with and without new-onset ATA. The factors associated with new-onset ATA were examined using univariate and multivariable analyses. RESULTS: Thirteen (13) (5.5%) patients experienced ATA during follow-up (mean, 21±14 months). Compared with patients without new-onset ATA, patients with new-onset ATA were older (48±18 vs 66±11 years; p<0.001) and had high brain natriuretic peptide (BNP) levels (36±36 vs 177±306 pg/mL; p<0.001). On multivariable analysis, BNP ≥40 pg/mL before ASD closure was associated with new-onset ATA after adjusting for age (OR, 4.91; 95% CI, 1.22-19.8; p=0.025). CONCLUSION: Patients with BNP levels >40 pg/mL before transcatheter ASD closure may have a higher risk of developing new-onset ATA.


Subject(s)
Cardiac Catheterization , Heart Septal Defects, Atrial , Adolescent , Adult , Cardiac Catheterization/adverse effects , Heart Atria/diagnostic imaging , Heart Septal Defects, Atrial/epidemiology , Heart Septal Defects, Atrial/surgery , Humans , Tachycardia/epidemiology , Tachycardia/etiology , Treatment Outcome
13.
Circulation ; 140(6): 487-499, 2019 08 06.
Article in English | MEDLINE | ID: mdl-31170826

ABSTRACT

BACKGROUND: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. METHODS: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. RESULTS: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. CONCLUSIONS: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.


Subject(s)
Hypertrophy, Left Ventricular/physiopathology , Neutrophils/physiology , Wnt-5a Protein/physiology , Animals , Aorta, Thoracic , Chemotaxis, Leukocyte , Constriction , Heart Failure/etiology , Heart Failure/physiopathology , Hypertrophy, Left Ventricular/etiology , Hypertrophy, Left Ventricular/immunology , Inflammation , Leukocyte Reduction Procedures , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardial Infarction/complications , Myocardial Infarction/physiopathology , Pressure , Recombinant Proteins/metabolism , Specific Pathogen-Free Organisms , Stress, Mechanical , Ventricular Remodeling/genetics , Wnt-5a Protein/biosynthesis , Wnt-5a Protein/deficiency , Wnt-5a Protein/genetics
14.
Circ Res ; 116(4): 612-23, 2015 Feb 13.
Article in English | MEDLINE | ID: mdl-25563839

ABSTRACT

RATIONALE: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. OBJECTIVE: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. METHODS AND RESULTS: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. CONCLUSIONS: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.


Subject(s)
Adventitia/metabolism , Aorta, Thoracic/metabolism , Aortic Aneurysm, Thoracic/metabolism , Aortic Dissection/metabolism , Aortic Rupture/metabolism , Chemokine CXCL1/metabolism , Granulocyte Colony-Stimulating Factor/metabolism , Neutrophil Activation , Neutrophil Infiltration , Neutrophils/metabolism , Acute Disease , Adventitia/diagnostic imaging , Aged , Aminopropionitrile/analogs & derivatives , Aortic Dissection/chemically induced , Aortic Dissection/diagnostic imaging , Aortic Dissection/drug therapy , Angiotensin II , Animals , Antibodies, Monoclonal/pharmacology , Aorta, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/chemically induced , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/drug therapy , Aortic Rupture/chemically induced , Aortic Rupture/diagnostic imaging , Aortic Rupture/prevention & control , Aortography , Chemokine CXCL12/metabolism , Chemotaxis, Leukocyte , Dilatation, Pathologic , Disease Models, Animal , Female , Humans , Inflammation Mediators/metabolism , Interleukin-6/blood , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/blood , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neutrophil Activation/drug effects , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Neutrophils/transplantation , Receptors, Interleukin-8B/antagonists & inhibitors , Receptors, Interleukin-8B/metabolism , Signal Transduction , Time Factors
15.
Am J Physiol Heart Circ Physiol ; 310(8): H1003-14, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26873964

ABSTRACT

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.


Subject(s)
Caloric Restriction , Complement Activation , Complement C3/metabolism , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/enzymology , Sirtuin 1/metabolism , Animals , Antioxidants/pharmacology , Cells, Cultured , Complement C3/deficiency , Complement C3/genetics , Complement C3/immunology , Disease Models, Animal , Genotype , Isolated Heart Preparation , Mice, Inbred C57BL , Mice, Knockout , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress , Phenotype , Phosphorylation , Rats, Sprague-Dawley , Resveratrol , Sirtuin 1/deficiency , Sirtuin 1/genetics , Stilbenes/pharmacology , Time Factors , Ventricular Function, Left
16.
Circ Res ; 114(4): 637-49, 2014 Feb 14.
Article in English | MEDLINE | ID: mdl-24366170

ABSTRACT

RATIONALE: Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. OBJECTIVE: We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. METHODS AND RESULTS: Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosis factor-α, interleukin [IL]-6, and IL-1ß), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1ß-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. CONCLUSIONS: This study is the first to identify a critical role for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after myocardial infarction.


Subject(s)
Endothelial Cells/immunology , Killer Cells, Natural/immunology , Myocardial Infarction/immunology , Pneumonia/immunology , Pulmonary Alveoli/immunology , Pulmonary Edema/immunology , Adoptive Transfer , Animals , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cell Membrane Permeability/immunology , Female , Green Fluorescent Proteins/genetics , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Killer Cells, Natural/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/complications , Neutrophils/immunology , Neutrophils/pathology , Pneumonia/complications , Pneumonia/pathology , Pulmonary Alveoli/pathology , Pulmonary Edema/complications , Pulmonary Edema/pathology
17.
Heart Vessels ; 30(2): 186-92, 2015 Mar.
Article in English | MEDLINE | ID: mdl-24493327

ABSTRACT

The proportion of elderly acute coronary syndrome (ACS) patients who receive optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) and whether OMT affects their long-term outcomes remain unclear. We retrospectively investigated 405 ACS patients who underwent stent implantation between 2005 and 2009, and compared the outcomes between patients <80 years of age vs. ≥80 years of age. The prescription rate of the recommended medical agents for ACS in both groups during hospitalization and 2 years after admission was also retrieved. Among the enrolled study population, 75 patients (19%) were aged ≥80 years. These elderly patients had a higher 2-year mortality compared with patients aged <80 years group. The prescription rate of beta-blockers, angiotensin-blocking drugs, and statins tended to be lower in patients aged ≥80 years than in those aged <80 years. Furthermore, among patients ≥80 years of age, those who received OMT had better clinical outcome of 2-year mortality compared to those without OMT. Elderly patients with ACS treated by PCI are at substantially higher risk of adverse events than younger patients. However, they are less likely to receive OMT. PCI with OMT might improve the clinical outcomes of elderly ACS patients.


Subject(s)
Acute Coronary Syndrome/therapy , Cardiovascular Agents/therapeutic use , Percutaneous Coronary Intervention , Practice Patterns, Physicians' , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/mortality , Age Factors , Aged , Aged, 80 and over , Disease-Free Survival , Drug Prescriptions , Drug Utilization Review , Female , Guideline Adherence , Humans , Japan , Kaplan-Meier Estimate , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/instrumentation , Percutaneous Coronary Intervention/mortality , Practice Guidelines as Topic , Practice Patterns, Physicians'/standards , Proportional Hazards Models , Retrospective Studies , Risk Factors , Stents , Time Factors , Treatment Outcome
18.
JACC Case Rep ; 29(5): 102221, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38464796

ABSTRACT

A 24-year-old woman with chronic active Epstein-Barr virus (CAEBV) infection successfully underwent coronary artery bypass grafting for triple coronary arteries with chronic total occlusion and aneurysms. This case underscores the importance of accurate assessment and treatment of coronary artery lesions in patients with CAEBV infection.

19.
Adv Biol (Weinh) ; 8(7): e2300512, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38684458

ABSTRACT

The phenomenon of sex chromosome loss from hematopoietic cells is an emerging indicator of biological aging. While many methods to detect this loss have been developed, enhancing the field, these existing methods often suffer from being labor-intensive, expensive, and not sufficiently sensitive. To bridge this gap, a novel and more efficient technique is developed, named the SinChro assay. This method employs multiplexed single-cell droplet PCR, designed to detect cells with sex chromosome loss at single-cell resolution. Through the SinChro assay, the age-dependent increase in Y chromosome loss in male blood is successfully mapped. The age-dependent loss of the X chromosome in female blood is also identified, a finding that has been challenging with existing methods. The advent of the SinChro assay marks a significant breakthrough in the study of age-related sex mosaicism. Its utility extends beyond blood analysis, applicable to a variety of tissues, and it holds the potential to deepen the understanding of biological aging and related diseases.


Subject(s)
Chromosomes, Human, Y , Mosaicism , Humans , Male , Female , Chromosomes, Human, Y/genetics , Chromosomes, Human, X/genetics , Single-Cell Analysis/methods , Aging/genetics , Sex Chromosome Aberrations
20.
J Mol Cell Cardiol ; 62: 24-35, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23644221

ABSTRACT

Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3 days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M1 and M2 macrophages, respectively, based on surface-marker expression. M1 macrophages dominated at 1-3 days post-MI, whereas M2 macrophages represented the predominant macrophage subset after 5 days. The M2 macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M1 macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4(+) T cells, whereas Th2 and Th17 cells were minor populations. CD8(+) T cells, γδT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies.


Subject(s)
Macrophages/cytology , Myocardial Infarction/immunology , Animals , Flow Cytometry , Kruppel-Like Factor 4 , Leukocyte Common Antigens/metabolism , Leukocytes/cytology , Leukocytes/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL
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