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Molecular Metabolism Jun 2024Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as...
OBJECTIVE
Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as powerful regulators in the progression of cardiac diseases. However, the functions of seRNAs in DbCM have not been fully elucidated.
METHODS
Super enhancers and their associated seRNAs were screened and identified by H3K27ac ChIP-seq data in the Encyclopedia of DNA Elements (ENCODE) dataset. A dual-luciferase reporter assay was performed to analyze the function of super-enhancers on the transcription of peroxisome proliferator-activated receptor α-related seRNA (PPARα-seRNA). A DbCM mouse model was established using db/db leptin receptor-deficient mice. Adeno-associated virus serotype 9-seRNA (AAV9-seRNA) was injected via the tail vein to evaluate the role of seRNA in DbCM. The underlying mechanism was explored through RNA pull-down, RNA and chromatin immunoprecipitation, and chromatin isolation by RNA purification.
RESULTS
PPARα-seRNA was regulated by super-enhancers and its levels were increased in response to high glucose and palmitic acid stimulation in cardiomyocytes. Functionally, PPARα-seRNA overexpression aggravated lipid deposition, reduced glucose uptake, and repressed energy production. In contrast, PPARα-seRNA knockdown ameliorated metabolic disorder in vitro. In vivo, overexpression of PPARα-seRNA exacerbated cardiac metabolic disorder and deteriorated cardiac dysfunction, myocardial fibrosis, and hypertrophy in DbCM. Mechanistically, PPARα-seRNA bound to the histone demethylase KDM4B (Lysine-specific demethylase 4B) and decreased H3K9me3 levels in the promoter region of PPARα, ultimately enhancing its transcription.
CONCLUSIONS
Our study revealed the pivotal function of a super-enhancer-driven long noncoding RNA (lncRNA), PPARα-seRNA, in the deterioration of cardiac function and the exacerbation of metabolic abnormalities in diabetic cardiomyopathy, which recruited KDM4B to the promoter region of PPARα and repression of its transcription. This suggests a promising therapeutic strategy for the treatment of DbCM.
PubMed: 38950776
DOI: 10.1016/j.molmet.2024.101978 -
The Journal of Thoracic and... Jun 2024To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy(HCM) who develop left ventricular outflow tract(LVOT) obstruction.
OBJECTIVE
To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy(HCM) who develop left ventricular outflow tract(LVOT) obstruction.
METHODS
We reviewed HCM patients with LVOT obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction, documented up to 7.6 years (IQR,6.3-9.4) before the operation, a comparison was made with 78 nonobstructive HCM patients over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups.
RESULTS
The median interval between echocardiographic assessments was 7.5 years (IQR,6.3-8.1) among obstructive versus 7.3 years (IQR,6.2-9.0) in nonobstructive patients. Obstructive patients were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both p<0.001), but the magnitude of increase was not different between groups (p=0.130). Obstructive patients exhibited a greater increase in left ventricular (LV) mass (p<0.001) compared to nonobstructive patients (p=0.004). Aortic angulation significantly increased in 4 of the 5 measurements(all p<0.001) in obstructive patients, while nonobstructive patients showed no change. Anterior and posterior mitral valve(MV) leaflet lengths and coaptation lengths remained similar in both groups over time.
CONCLUSIONS
The development of LVOT obstruction in patients with HCM was associated with progressive LVOT angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the MV leaflet morphology.
PubMed: 38950769
DOI: 10.1016/j.jtcvs.2024.06.022 -
PloS One 2024The objective of this study was to retrospectively assess the effect of Radiofrequency Volumetric Tissue Reduction (RFVTR) on hypertrophic turbinates and clinical...
OBJECTIVE
The objective of this study was to retrospectively assess the effect of Radiofrequency Volumetric Tissue Reduction (RFVTR) on hypertrophic turbinates and clinical outcome in brachycephalic dogs when included in multi-level surgery (MLS).
STUDY DESIGN
Clinical retrospective multicenter study.
ANIMALS
132 client-owned brachycephalic dogs.
METHODS
132 brachycephalic dogs with high-grade Brachycephalic Obstructive Airway Ayndrome (BOAS) and hypertrophic turbinates were treated with RFVTR as part of MLS of the upper airways. Intranasal obstruction was evaluated by computer tomography (CT) and antero-/retrograde rhinoscopy before and 6 months after RFVTR. The clinical records, the CT images and the rhinoscopy videos were reviewed and clinical evolution was evaluated using a standardized questionnaire. The data was scored semi-quantitatively.
RESULTS
In this study, 132 patients were included for a follow-up period of 120 weeks. RFVTR resulted in minor complications, including serous nasal discharge within the first postoperative week in all dogs, and intermittent nasal congestion between 3-8 weeks after treatment in 24.3% of the patients. Rhinoscopy and CT follow-ups were available for 33 patients. Six months after treatment intranasal airspace was increased (p = 0.002) and the presence and overall amount of mucosal contact points was reduced (p = 0.039).
CONCLUSION
MLS with RFVTR led to a significant reduction in turbinate volume at the 6-month follow-up examination and significant clinical improvement over a long-term period of 120 weeks. This suggests the viability of RFVTR as a turbinate-preserving treatment for intranasal obstruction in dogs with BOAS.
CLINICAL SIGNIFICANCE
RFVTR is a minimally invasive turbinoplasty technique for intranasal obstruction in dogs with BOAS and can be included in MLS without increasing complication rates.
Topics: Animals; Dogs; Turbinates; Retrospective Studies; Dog Diseases; Male; Female; Nasal Obstruction; Hypertrophy; Tomography, X-Ray Computed; Treatment Outcome; Airway Obstruction
PubMed: 38950052
DOI: 10.1371/journal.pone.0306391 -
Journal of Visualized Experiments : JoVE Jun 2024Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The...
Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The pathogenesis of RV failure is complex and remains inadequately understood. To identify new therapeutic strategies for the treatment of RV failure, robust and reproducible animal models are essential. Models of pulmonary trunk banding (PTB) have gained popularity, as RV function can be assessed independently of changes in the pulmonary vasculature. In this paper, we present a murine model of RV pressure overload induced by PTB in 5-week-old mice. The model can be used to induce different degrees of RV pathology, ranging from mild RV hypertrophy to decompensated RV failure. Detailed protocols for intubation, PTB surgery, and phenotyping by echocardiography are included in the paper. Furthermore, instructions for customizing instruments for intubation and PTB surgery are given, enabling fast and inexpensive reproduction of the PTB model. Titanium ligating clips were used to constrict the pulmonary trunk, ensuring a highly reproducible and operator-independent degree of pulmonary trunk constriction. The severity of PTB was graded by using different inner ligating clip diameters (mild: 450 µm and severe: 250 µm). This resulted in RV pathology ranging from hypertrophy with preserved RV function to decompensated RV failure with reduced cardiac output and extracardiac manifestations. RV function was assessed by echocardiography at 1 week and 3 weeks after surgery. Examples of echocardiographic images and results are presented here. Furthermore, results from right heart catheterization and histological analyses of cardiac tissue are shown.
Topics: Animals; Mice; Disease Models, Animal; Hypertrophy, Right Ventricular; Pulmonary Artery; Heart Failure; Ventricular Dysfunction, Right; Male; Echocardiography; Mice, Inbred C57BL
PubMed: 38949319
DOI: 10.3791/66851 -
BioRxiv : the Preprint Server For... Jun 2024We take a unique approach to understanding the causes of podocyte injury in collagen IV nephropathies, a crucial step in developing targeted therapies for conditions...
RATIONALE
We take a unique approach to understanding the causes of podocyte injury in collagen IV nephropathies, a crucial step in developing targeted therapies for conditions like Alport Syndrome.
OBJECTIVES
We characterize the structural, functional, and biophysical properties of glomerular capillaries and podocytes in mice and analyze kidney cortex transcriptional profiles at various disease stages. We investigate the effects of the ER stress mitigator TUDCA on these parameters. Furthermore, we used human FSGS associated podocyte enriched genes to identify molecular pathways rescued by TUDCA thereby offering potential therapeutic targets for Alport Syndrome.
FINDINGS
We find a clear disease progression timeline in mice. Podocyte injury develops by 3 months, with glomeruli reaching maximum deformability at 4 months, associated with a 40% loss of podocytes. This is followed by progressive stiffening of glomerular capillaries, increasing proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis from months 4 to 8. Bulk RNA sequencing at 2, 4, and 7 months reveals a progressive increase in expression of genes related to cytokine and chemokine signaling, matrix and cell injury, and activation of the TNF pathway, similar to observations in a NEPTUNE FSGS cohort. Podocyte-enriched genes from FSGS patients mapped to mice found that TUDCA, which mitigated glomerular and renal injury suppressed molecular pathways associated with extracellular matrix and basement membrane synthesis, podocyte stress and hypertrophy.
CONCLUSIONS
We uncover two distinct phases of nephropathy progression. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. The response of podocytes to TUDCA treatment provides novel insights into downstream signaling pathways, offering potential therapeutic targets for treating Alport and related nephropathies.
PubMed: 38948788
DOI: 10.1101/2024.02.26.582201 -
BioRxiv : the Preprint Server For... Oct 2023Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm...
Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of in nephron progenitor cells. is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
PubMed: 38948707
DOI: 10.1101/2023.10.18.562984 -
Frontiers in Endocrinology 2024Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their...
OBJECTIVES
Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats.
METHODS
Eight-week-old male Sprague-Dawley rats were fed either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT.
RESULTS
HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; = 0.004) and larger median size of BMAds in the proximal tibia (815 µm vs 592 µm, respectively; = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage ( < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus ( < 0.001) and higher in 8-week-old compared to 32-week-old rats ( < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, = 0.005) and negatively with humeral BMGU (r = -0.63, = 0.02). HFD significantly reduced trabecular number ( < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher ( = 0.008) than in the HFD group.
CONCLUSION
In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.
Topics: Animals; Male; Rats, Sprague-Dawley; Rats; Adiposity; Diet, High-Fat; Physical Conditioning, Animal; Bone Marrow; Glucose; Obesity; Adipocytes
PubMed: 38948514
DOI: 10.3389/fendo.2024.1422869 -
Cancer Innovation Jun 2024Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular... (Review)
Review
Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.
PubMed: 38947757
DOI: 10.1002/cai2.114 -
IDCases 2024Kaposi sarcoma is an indolent angio-proliferative spindle- cell tumor derived from endothelial and immune cells infected with Human herpes virus type 8(HHV-8). In the...
Kaposi sarcoma is an indolent angio-proliferative spindle- cell tumor derived from endothelial and immune cells infected with Human herpes virus type 8(HHV-8). In the era of highly active antiretroviral (HAART), Kaposi sarcoma is a rare form of initial presentation of HIV infection [1]. The author presents a case of diffuse gingival hypertrophied Kaposi sarcoma in 18-year-old male newly diagnosed RVI patient. After confirming the diagnosis patient started on HAART and mouth care. Surgical excision is the first line of treatment with HAART, since this patient has low CD4 count of 30 cells/mm3 which will complicate the surgery. So, we are waiting for CD4 count to increase above 200 cells/mm3 to undergo surgical excision. The case is representative of HIV complexity and aimed to bring awareness of unusual presentation of HIV.This case also reminds us how important early initiation of HAART is.
PubMed: 38947560
DOI: 10.1016/j.idcr.2024.e02003 -
European Review For Medical and... Jun 2024A condition known as ligamentum flavum (LF) hypertrophy occurs when the ligamentum flavum (LF) swells as a result of pressures applied to the spine. Among the elderly... (Observational Study)
Observational Study
OBJECTIVE
A condition known as ligamentum flavum (LF) hypertrophy occurs when the ligamentum flavum (LF) swells as a result of pressures applied to the spine. Among the elderly population, lumbar spinal stenosis is a major cause of pain and disabilities. Numerous studies indicate that lumbar spinal stenosis etiology involves the ligamentum flavum in a major way. This study looks into the relationship between low back pain and ligamentum flavum thickening.
PATIENTS AND METHODS
The imaging tests and case histories of all patients with low back pain who had consecutive magnetic resonance imaging exams performed at the Prince Sattam University and King Khalid hospitals in Al Kharj City will serve as the basis for this retrospective observational study. A radiologist utilized the Pfirrmann grading system, which is based on spinal levels starting from the first lumbar to the first sacral vertebrae, to measure the thickness of the ligamentum flavum in all cases who underwent magnetic resonance imaging (MRI). A correlation between age, hypertrophy of LF, and low back pain was investigated.
RESULTS
There were 79 participants in the study, ages ranging from 21 to 82, 49 of which were men. The patients' average age was 54 years, and 62% of them were men. We found no appreciable variations in LF thickness according to gender. At the L4-L5 and L5-S1 levels, the left LF was noticeably thicker than the right. Moreover, there was a significant difference (p < 0.05) in the bilateral LF thicknesses at L5-S1 compared to the comparable sides at L4-L5.
CONCLUSIONS
By evaluating the thickness of LF on magnetic resonance images, we discovered that it may be closely associated with the etiology of pain processes in the spine.
Topics: Humans; Ligamentum Flavum; Low Back Pain; Hypertrophy; Male; Middle Aged; Female; Aged; Magnetic Resonance Imaging; Retrospective Studies; Adult; Aged, 80 and over; Young Adult; Lumbar Vertebrae; Spinal Stenosis
PubMed: 38946379
DOI: 10.26355/eurrev_202406_36458