Biology subjects

Komuro, I.

Publications and source records attributed to Komuro, I..

8 recordsLinked to original sources

bioRxiv2026

The REFLEX system enables in vivo identification of perivascular angiogenic macrophages in the heart

Direct identification of physically interacting cells in vivo remains challenging because conventional interactome analyses infer signaling partners from transcriptomes and cannot reveal which cells are in direct contact. In pressure-overload induced cardiac remodeling, VEGF-A plays a central role in the maintenance of vascular integrity and cardiac function. However, the cell type which produces VEGF-A and how the VEGF-A peptide is delivered to vascular endothelial cells remains unclear. Here, we developed a genetically encoded platform that combines REFLEX mice with HUNTERuni-seq, enabling unbiased detection and transcriptional profiling of the cells that physically interact with vascular endothelial cells. The REFLEX and HUNTERuni-seq approach identified subpopulations of Vegfa positive macrophages which we named perivascular angiogenic macrophages (PVAMs). Although the amount of VEGF-A in PVAMs is small, loss of VEGF-A in PVAMs impaired angiogenesis and systolic function during pressure overload. We additionally show that direct contact between PVAMs and endothelial cells is critical for the delivery of VEGF-A to endothelial cells. Conventional interactome analysis predicted that cardiomyocytes as dominant sources of VEGF-A in the heart. However, cardiomyocyte Vegfa deletion had no effect on capillary density nor systolic function in a model of heart failure. These results suggest that VEGF-A signaling does not rely on free diffusion through the interstitium and that cellular proximity and physical contact between PVAMs and endothelial cells are the key determinants of effective signal delivery. Together, these findings establish REFLEX and HUNTERuni-seq as a versatile platform for uncovering biologically critical cell-to-cell interactions and provide new insight into intercellular communication in pathological tissue contexts.

cell biology↗

bioRxiv2023

Cardiomyocyte transcriptomic signatures in response to Trypanosoma cruzi infection underpin Chagas cardiomyopathy progression.

Chagas disease can lead to life-threatening cardiac manifestations that occur more frequently in geographic areas more prevalent with the TcI/II circulating genetic strains. To elucidate the differential transcriptomic signatures of the cardiomyocyte resulting from infection with TcI/II or TcVI T. cruzi strains and explore their relationships with pathogenesis, HL-1 rodent cardiomyocytes were infected with TcI/II or TcVI T. cruzi trypomastigotes. RNA was isolated serially post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change [≥]2 or [≤] 0.5) highlighted the over-represented biological pathways. We found that Oxidative stress-related GO terms, Hypertrophy model, Apoptosis, and MAPK signaling pathways (all with p<0.01) were upregulated. Glutathione and one-carbon metabolism pathway, and Cellular nitrogen compound metabolic process GO term (all with p <0.001) were upregulated exclusively in the cardiomyocytes infected with the TcI/II strains. Upregulation in the oxidative stress-related and hypertrophic responses are shared hallmarks with viral myocarditis, another inflammatory cardiac pathology. Nitrogen metabolism upregulation and Glutathione metabolism imbalance may implicate the relation of nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of chagasic cardiomyopathy development. ImportanceChagas disease affects more than 6 million people worldwide. One-third of those chronically infected will develop the life-threatening condition Chagas Cardiomyopathy (CCM). Trypanosoma cruzi (T. cruzi), grouped based on their genetic variability into six discrete typing units (DTU), are associated with DTU-specific clinical phenotypes. The diverse genetic make-up of parasite virulence factors shall evoke unique host defense responses of variable magnitude, collectively affecting the phenotypic expression of CCM. To address this, we performed a transcriptome analysis of cardiomyocytes infected with three different T. cruzi strains each belonging to a different DTU. As a result, we were able to point out dysregulation in nitrogen metabolic processes, Glutathione, and one-carbon metabolism pathways as main features in the host response against cardiomyopathy-prone T. cruzi strains. Further research on these pathways could serve not only in the lookout for progression biomarkers but also in the lead toward the discovery of new therapeutic targets.

cell biology↗

bioRxiv2022

Inverse Agonist Activity of Angiotensin II Receptor Blocker Is Crucial for Prevention of Aortic Aneurysm Formation in Marfan Syndrome

BackgroundMarfan syndrome (MFS), an inherited disorder caused by FBN1 gene mutations, causes fatal aortic aneurysm. Selective angiotensin II (Ang II) type 1 (AT1) receptor blockade is a preventive option for patients with MFS aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an AT1 receptor blocker (ARB) losartan on aortic aneurysm growth is equivalent to that of {beta}-blockers. At present, several ARBs are clinically available, and they have drug-specific differences in pharmacological properties. Especially, inverse agonism of ARBs has potential benefits for cardiovascular protection, but its impact on MFS aortopathy remains poorly understood. MethodsCandesartan-7H is a candesartan derivative which lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for AT1 receptor. Candesartan cilexetil (1 mg/kg/day), candesartan-7H (1 mg/kg/day or 20 mg/kg/day), or vehicle was administered to Fbn1C1041G/+ mice, and aortic aneurysm formation was analyzed using echocardiography, histological staining, and in situ MMP assay. Activation of TGF-{beta} signaling and mechanosensitive signaling was studied using western blot and immunohistochemical analysis. ResultsCandesartan cilexetil (1 mg/kg/day) and candesartan-7H (20 mg/kg/day) lowered blood pressures equally in Fbn1C1041G/+ mice, but that candesartan-7H (1 mg/kg/day) did not. Aortic aneurysmal progression in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-{beta} signaling activation in Fbn1C1041G/+ mice was significantly suppressed by treatment with candesartan cilexetil (1 mg/kg/day), but not by candesartan-7H even at 20 mg/kg/day. In addition, candesartan cilexetil, but not candesartan-7H, inhibited up-regulation of mechanical stress-responsive transcriptional factor Egr-1 in ascending aorta of Fbn1C1041G/+ mice. ConclusionsOur findings support a crucial role of inverse agonist activity of ARB for prevention of mechanical stress-induced AT1 receptor activation and aortic aneurysm formation in MFS mice.

pharmacology and toxicology↗

bioRxiv2022

Aberrant mechanosensitive signaling underlies activation of vascular endothelial xanthine oxidoreductase that promotes aortic aneurysm formation in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined. We found a significant increase in reactive oxygen species (ROS) generation in ascending aorta of MFS patients and MFS mice harboring the Fbn1 mutation (C1039G), which was associated with up-regulation of xanthine oxidoreductase (XOR) protein in aortic endothelial cells (ECs). Mechanosensitive signaling involving focal adhesion kinase (FAK)-p38 mitogen-activated protein kinase (MAPK) and early growth response-1 (Egr- 1) was aberrantly activated in ascending aorta of Fbn1C1039G/+ mice, and mechanical stress on human aortic ECs up-regulated XOR expression through FAK-p38 MAPK activation and Egr-1 up-regulation. Inhibition of XOR function by ECs-specific disruption of Xdh gene or by systemic administration of XOR inhibitor febuxostat in Fbn1C1039G/+ mice suppressed ROS generation, FAK-p38 MAPK activation, and Egr-1 up-regulation, leading to attenuation of aortic aneurysm formation. These findings unveil aberrant mechanosensitive signaling in vascular ECs triggering endothelial XOR activation and ROS generation as a culprit underlying the pathogenesis of aortic aneurysm formation in MFS, and highlight a drug repositioning approach using a uric acid lowering drug febuxostat as a potential therapy for MFS.

pathology↗

bioRxiv2021

Deep learning-based chest X-ray age serves as a novel biomarker for cardiovascular aging

Chest X-ray (CXR) is one of the most commonly performed medical imaging tests. Although aging, sex and disease status have been known to cause changes in CXR findings, the extent of these effects has not been fully characterized. Here, we present a deep neural network (DNN) model trained using more than 100,000 CXRs to estimate the patients age and sex solely from CXRs. Our DNN exhibited high performance in terms of estimating age and sex, with Pearsons correlation coefficient between the actual and estimated age of above 0.9 and an area under the ROC curve of 0.98 for sex estimation. The difference between the actual and estimated age is large in CXRs with abnormal findings, suggesting that the estimated age ("CXR age") can be a biomarker for disease status. Furthermore, by applying our DNN to CXRs of consecutive 1,562 hospitalized heart failure patients, we demonstrated that an elevated CXR age is not only associated with aging-related diseases, such as hypertension and atrial fibrillation, but also a worse outcome of heart failure. Given these results, our new concept "CXR age" serves as a novel biomarker for cardiovascular aging and can help clinicians to predict, prevent, and manage cardiovascular diseases.

bioinformatics↗

bioRxiv2019

Population-specific and transethnic genome-wide analyses reveal distinct and shared genetic risks of coronary artery disease

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.

genetics↗

bioRxiv2019

Transethnic meta-analysis of genome-wide association studies identifies three new loci and characterizes population-specific differences for coronary artery disease

BackgroundGenome-wide association studies (GWAS) provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. GWAS in diverse populations have the potential to advance our understanding of CAD.\n\nMethods and ResultsWe conducted two GWAS for CAD in the Japanese population, which included 12,494 cases and 28,879 controls, and 2,808 cases and 7,261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the CARDIoGRAMplusC4D 1000 Genomes meta-analysis with UK Biobank. We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands and fat tissues in the development of CAD. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies, and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans.\n\nConclusionsWe identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

genetics↗

bioRxiv2018

PTGER2-β-Catenin Axis Links High Salt Environments to Autoimmunity by Balancing IFNγ and IL-10 in FoxP3+ Regulatory T cells

Foxp3+ regulatory T cells (Tregs) are the central component of peripheral immune tolerance. While dysregulation of the Treg cytokine signature has been observed in autoimmune diseases such as multiple sclerosis (MS) and type 1 diabetes, the regulatory mechanisms balancing pro- and anti-inflammatory cytokine production are not known. Here, we identify imbalance between IFN{gamma} and IL-10 as a shared Treg signature, present in patients with MS and under high salt conditions. By performing RNA-seq analysis on human Treg subpopulations, we identify {beta}-catenin as a key regulator that controls the expression of IFN{gamma} and IL-10. The activated {beta}-catenin signature is enriched specifically in IFN{gamma}+Tregs in humans, and this was confirmed in vivo with Treg-specific {beta}-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional, IFN{gamma}-producing, Treg phenotype. Moreover, we identify PTGER2 as a major factor balancing IFN{gamma} and IL-10 production in the context of a high salt environment, with skewed activation of the {beta}-catenin/SGK1/Foxo axis in IFN{gamma}+Tregs. These findings identify a novel molecular mechanism underlying inflammatory Tregs in human autoimmune disease and reveal a new role for a PTGER2-{beta}-catenin loop in Tregs linking environmental high salt conditions to autoimmunity.

immunology↗