A5015886646- Cardiomyopathy and Myosin Studies
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Viral Infections and Immunology Research
- Pluripotent Stem Cells Research
- Cardiac Imaging and Diagnostics
- RNA Research and Splicing
- Erythropoietin and Anemia Treatment
- Congenital heart defects research
- Protease and Inhibitor Mechanisms
- ATP Synthase and ATPases Research
- Cardiovascular Effects of Exercise
- Acute Myocardial Infarction Research
- 3D Printing in Biomedical Research
- Protein Kinase Regulation and GTPase Signaling
- Cardiac Fibrosis and Remodeling
- Coronary Interventions and Diagnostics
- Signaling Pathways in Disease
- Cardiovascular Function and Risk Factors
- Cardiac electrophysiology and arrhythmias
- Immune Response and Inflammation
- Muscle Physiology and Disorders
- Atherosclerosis and Cardiovascular Diseases
- Blood Coagulation and Thrombosis Mechanisms
- NF-κB Signaling Pathways
Osaka University
2014-2024
Soka University
2024
Kansai Rosai Hospital
2005
Significance We identified hypoxia-inducible domain family, member 1A (Higd1a) as a positive regulator of cytochrome c oxidase (CcO). CcO, the terminal component mitochondrial electron transfer system, reductively converts molecular oxygen to water coupled pump protons across inner membrane. Higd1a is transiently induced under hypoxic conditions and increases CcO activity by directly interacting with in vicinity its active center. Induction leads increased consumption subsequent ATP...
Abstract Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. However, underlying mechanisms remain largely unknown. Here we identify PDZ LIM domain 5 (Pdlim5) as a novel substrate show that it plays critical role inhibition migration. directly phosphorylates Pdlim5 at Ser177. Exogenous expression phosphomimetic...
Significance We developed a sensitive method to assess the activity of oxidative phosphorylation in living cells using FRET-based ATP biosensor. then revealed that G0/G1 switch gene 2, protein rapidly induced by hypoxia, increases mitochondrial production interacting with F o 1 -ATP synthase and protects from critical energy crisis.
Scientific Report7 March 2014Open Access Source Data Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2 Yasunori Shintani Corresponding Author William Harvey Research Institute, Barts and The London School Medicine Dentistry, Queen Mary University London, UK Department Medical Biochemistry, Osaka Graduate Medicine, Suita, Japan Search for more papers this author Hannes CA Drexler Bioanalytical Mass...
Cardiac-specific myosin light chain kinase (cMLCK), encoded by
Although high-throughput sequencing can elucidate the genetic basis of hereditary cardiomyopathy, direct interventions targeting pathological mutations have not been established. Furthermore, it remains uncertain whether homology-directed repair (HDR) is effective in non-dividing cardiomyocytes. Here, we demonstrate that HDR-mediated genome editing using CRISPR/Cas9 Transduction adeno-associated virus (AAV) containing sgRNA and template into cardiomyocytes constitutively expressing Cas9...
Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts phenotypic analysis for proof concept gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression plakophilin-2 from patient AC...
Abstract Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain structural integrity tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly an autosomal dominant manner. Here, we identified a homozygous stop-gain (c.C355T, p.R119X) led to complete desmoglein-2 deficiency patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition proteins, disrupted intercalated disk structures myocardium....
Abstract Under hypertrophic stimulation, cardiomyocytes enter a hypermetabolic state and accelerate biomass accumulation. Although the molecular pathways that regulate protein levels are well-studied, functional implications of RNA accumulation its regulatory mechanisms in remain elusive. Here, we have elucidated quantitative kinetics through single cell imaging c-Myc ( Myc )-mediated analytical model using cultured cardiomyocytes. Nascent labeling combined with demonstrated significantly...
Abstract Post-mitotic cardiomyocytes have been considered to be non-permissive precise targeted integration including homology-directed repair (HDR) after CRISPR/Cas9 genome editing. Here, we demonstrate that direct delivery of large amounts transgene encoding guide RNA (gRNA) and template DNA via intra-ventricular injection adeno-associated virus (AAV) promotes replacement in adult murine expressing Cas9. Neither systemic AAV nor adenovirus integration, suggesting high copy numbers...
Estimation of dynamic change crossbridge formation in living cardiomyocytes is expected to provide crucial information for elucidating cardiomyopathy mechanisms, efficacy an intervention, and others. Here, we established assay system dynamically measure second harmonic generation (SHG) anisotropy derived from myosin filaments depended on their status pulsating cardiomyocytes. Experiments utilizing inheritable mutation that induces excessive myosin-actin interactions revealed the correlation...
Abstract Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease‐specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive (RCM), a rare and intractable cardiomyopathy, remains at experimental stage because there currently no established method to replicate hallmark phenotype RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs patient with early childhood‐onset RCM harboring...
Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current assessment paradigms (CiPA and JiCSA), necessitating 2D monolayer tissue, we integrated the TW multi-electrode array. This gave rise hiPSC-derived closed-loop tissue (iCT), enabling spontaneous initiation swift pacing...
Although the elevation of circulating plasma matrix metalloproteinase (MMP)-9 levels in patients with acute myocardial infarction (AMI) has been documented, origin MMP-9 remains unclear.Plasma both peripheral circulation and coronary arteries were measured AMI (n=23) stable angina pectoris (SAP, n=10) during percutaneous intervention (PCI) a distal protection device. Blood samples collected from femoral artery (FA) before (Initial) after (Second) dilation culprit lesion. Coronary sinus blood...
Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective probably because of platelet activation a lack knowledge regarding the optimal dose. In contrast, small pilot study low-dose improvement in left ventricular function without adverse cardiovascular events.Methods Results:We performed multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding to clarify...
Background: The Δ160E mutation in TNNT2 , which encodes troponin T, is a rare pathogenic variant identified patients with hypertrophic cardiomyopathy and associated poor prognosis. Thus, convenient human model recapitulating the pathological phenotype caused by required for therapeutic development. Methods: We heterozygous in-frame deletion (c.478_480del, p.Δ160E) patient familial showing progressive left ventricular systolic dysfunction, leading to advanced heart failure. To investigate...
Study investigators encountered a female Becker muscular dystrophy (BMD) carrier with advanced heart failure (HF) and identified stop-gain variant in procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) as potential second-hit variant. Isogenic induced pluripotent stem cells (iPSCs) dominant expression of WT-DMD, Δ45-48-DMD, or Δ45-48-DMD corrected PLOD3 were established. Microforce testing using 3-dimensional self-organized tissue rings (SOTRs) generated from iPSC-derived...
A 70-year-old man with dyspnea was admitted to our department and received standard therapy for recurrent heart failure. He diagnosed polycystic kidney disease (PKD) in his thirties hemodialysis 4 years before undergoing renal transplantation at age 45. Although left ventricular ejection fraction (LVEF) preserved 50s, LVEF decreased progressively from 61% 24%, while diastolic dimension (LVDd) increased 54 mm 65 between 63 69 of age. Right endomyocardial biopsy demonstrated myocardial...
Background Accurate prediction of both mortality and morbidity is significant importance, but it challenging in patients with severe heart failure. It especially difficult to detect the optimal time for implanting mechanical circulatory support devices such patients. We aimed analyze morphometric ultrastructure nuclear chromatin cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker predict poor outcome dilated cardiomyopathy...
Phospholamban p.Arg14del is reported to cause hereditary cardiomyopathy with malignant ventricular tachycardia (VT) and advanced heart failure. However, the clinical courses of Japanese patients phospholamban remain uncharacterized. We identified five this variant. All were diagnosed dilated (DCM), developed end-stage failure experienced VT requiring implantable cardioverter defibrillator discharge. Four survived after implantation a left assist device (LVAD), while one patient who refused...
Recent advances in genome analysis have enabled the identification of numerous distal enhancers that regulate gene expression various conditions. However, involved pathological conditions are largely unknown because lack vivo quantitative assessment enhancer activity live animals. Here, we established a noninvasive and imaging system for monitoring transcriptional identified novel stress-responsive Nppa Nppb, most common markers heart failure. The is 650-bp fragment within 50 kb Nppb loci. A...