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Arquivos Brasileiros de Cardiologia 2024The anthracycline chemotherapeutic antibiotic doxorubicin (DOX) can induce cumulative cardiotoxicity and lead to cardiac dysfunction. Long non-coding RNAs (lncRNAs) can...
BACKGROUND
The anthracycline chemotherapeutic antibiotic doxorubicin (DOX) can induce cumulative cardiotoxicity and lead to cardiac dysfunction. Long non-coding RNAs (lncRNAs) can function as important regulators in DOX-induced myocardial injury.
OBJECTIVE
This study aims to investigate the functional role and molecular mechanism of lncRNA OXCT1 antisense RNA 1 (OXCT1-AS1) in DOX-induced myocardial cell injury in vitro.
METHODS
Human cardiomyocytes (AC16) were stimulated with DOX to induce a myocardial cell injury model. OXCT1-AS1, miR-874-3p, and BDH1 expression in AC16 cells were determined by RT-qPCR. AC16 cell viability was measured by XTT assay. Flow cytometry was employed to assess the apoptosis of AC16 cells. Western blotting was used to evaluate protein levels of apoptosis-related markers. Dual-luciferase reporter assay was conducted to verify the binding ability between miR-874-3p and OXCT1-AS1 and between miR-874-3p and BDH1. The value of p<0.05 indicated statistical significance.
RESULTS
OXCT1-AS1 expression was decreased in DOX-treated AC16 cells. Overexpression of OXCT1-AS1 reversed the reduction of cell viability and promotion of cell apoptosis caused by DOX. OXCT1-AS1 is competitively bound to miR-874-3p to upregulate BDH1. BDH1 overexpression restored AC16 cell viability and suppressed cell apoptosis under DOX stimulation. Knocking down BDH1 reversed OXCT1-AS1-mediated attenuation of AC16 cell apoptosis under DOX treatment.
CONCLUSION
LncRNA OXCT1-AS1 protects human myocardial cells AC16 from DOX-induced apoptosis via the miR-874-3p/BDH1 axis.
Topics: Humans; Doxorubicin; RNA, Long Noncoding; Apoptosis; Myocytes, Cardiac; MicroRNAs; Antibiotics, Antineoplastic; Cell Survival; Reproducibility of Results; Blotting, Western; Flow Cytometry; RNA, Competitive Endogenous
PubMed: 38958296
DOI: 10.36660/abc.20230675 -
Veterinary Radiology & Ultrasound : the... Jul 2024Myocardial mapping in humans has been widely studied and applied to understand heart disease, facilitate early diagnosis, and determine therapeutic targets; however, the...
Multiparametric myocardial mapping using cardiac magnetic resonance imaging in healthy dogs: Reproducibility, repeatability, and differences across slices, segments, and sequences.
Myocardial mapping in humans has been widely studied and applied to understand heart disease, facilitate early diagnosis, and determine therapeutic targets; however, the reproducibility, repeatability, and protocol-dependent differences in myocardial mapping in dogs remain unknown, which limits its application in dogs. This study investigated the reproducibility and test-retest repeatability of myocardial mapping in dogs and evaluated the differences according to slice, segment, and sequence. Precontrast T1 (native T1), T2 (T2), and T2* relaxation time (T2*), and extracellular volume (ECV) were measured at the base, midventricle, and apex of the left ventricle in six healthy beagles. To compare the sequences, the saturation recovery-based (SMART1) and inversion recovery-based (MOLLI) sequences were used for native T1 and ECV mapping. The intraclass correlation coefficient was measured to evaluate reproducibility and repeatability using the coefficient of variation and Bland-Altman analysis. All parameters showed good to excellent intra- and interobserver reproducibility and test-retest repeatability. The apex slice showed the lowest repeatability among the slices, whereas ECV had the lowest repeatability among the parameters. Native T1, ECV, and T2* did not differ according to slice, but T2 significantly increased from the base to the apex. Native T1 was significantly higher in SMART1 than in MOLLI, whereas ECV did not differ between the two sequences. Our results suggest that myocardial mapping is applicable in dogs with high reproducibility and repeatability, although slice and sequence differences should be considered. This study can serve as a guide for myocardial mapping studies in dogs with heart disease.
PubMed: 38958215
DOI: 10.1111/vru.13406 -
Journal of Cell Science Jul 2024Cellular heterogeneity is a well-accepted feature of tissues, and both transcriptional and metabolic diversity have been revealed by numerous approaches, including...
Cellular heterogeneity is a well-accepted feature of tissues, and both transcriptional and metabolic diversity have been revealed by numerous approaches, including optical imaging. However, the high magnification objective lenses needed for high-resolution imaging provides information from only small layers of tissue, which can result in poor cell statistics. There is therefore an unmet need for an imaging modality that can provide detailed molecular and cellular insight within intact tissue samples in 3D. Using GFP-tagged GLUT4 as proof of concept, we present here a novel optical mesoscopy approach that allows precise measurement of the spatial location of GLUT4 within specific anatomical structures across the myocardium in ultrathick sections (5 mm x 5 mm x 3 mm) of intact mouse heart. We reveal distinct GLUT4 distribution patterns across cardiac walls and highlight specific changes in GLUT4 expression levels in response to high fat diet-feeding, and we identify sex-dependent differences in expression patterns. This method is applicable to any target that can be labelled for light microscopy, and to other complex tissues when organ structure needs to be considered simultaneously with cellular detail.
PubMed: 38958032
DOI: 10.1242/jcs.262146 -
Circulation Research Jul 2024PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial...
BACKGROUND
PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated.
METHOD
We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1).
RESULTS
PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45), particularly neutrophils (CD11b, Ly6g), to the myocardium.
CONCLUSIONS
Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.
PubMed: 38957990
DOI: 10.1161/CIRCRESAHA.124.324650 -
Clinical Nephrology. Case Studies 2024We investigated the pathogenesis of a perihilar variant of focal segmental glomerulosclerosis detected by kidney biopsy in a 16-year-old male. The disease was refractory...
Renal and cardiac biopsy findings in an adolescent patient with the 3243A>G mitochondrial DNA mutation: Favorable renal prognosis post renal transplantation from the mother.
We investigated the pathogenesis of a perihilar variant of focal segmental glomerulosclerosis detected by kidney biopsy in a 16-year-old male. The disease was refractory to steroid therapy, and at the second kidney biopsy, abnormal mitochondrial proliferation was newly observed in the podocytes. The patient also developed late-onset hearing loss and had a family history of diabetes, and genetic testing confirmed the mitochondrial DNA mutation 3243A>G (48%). Eight months after hemodialysis was started, encephalopathy occurred presumably due to rapid dehydration. After changing dialysis into continuous ambulatory peritoneal dialysis, encephalopathy was resolved, but the patient developed myocardial hypertrophy, probably because of the myocardial overreaction to congestion. A myocardial biopsy showed mitochondrial proliferation in the myocardium. After renal transplantation from his mother with a heteroplasmy of 4%, the cardiomyopathy improved, and the renal function has remained stable for 4 years. We speculated that the abnormal mitochondrial morphology in the kidney and heart may be characteristic of mitochondrial genetic disease, and renal transplantation from the mother with a low heteroplasmy was considered desirable for mitochondrial nephropathy with poor prognosis.
PubMed: 38957708
DOI: 10.5414/CNCS111422 -
Fundamental & Clinical Pharmacology Jul 2024Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β-adrenergic...
BACKGROUND
Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β-adrenergic receptor (β-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome.
OBJECTIVES
The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy.
METHODS
Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours.
RESULTS
The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β-AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels.
CONCLUSION
Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.
PubMed: 38956972
DOI: 10.1111/fcp.13026 -
Korean Circulation Journal Jun 2024Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show...
BACKGROUND AND OBJECTIVES
Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies.
METHODS
Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings.
RESULTS
The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes.
CONCLUSIONS
Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.
PubMed: 38956938
DOI: 10.4070/kcj.2024.0033 -
Scientific Reports Jul 2024The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in...
The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in subsequent stages of pulmonary arterial hypertension (PAH) to determine mechanisms responsible for LV mass loss in a monocrotaline-induced PAH rat model. LV myocardium samples collected from 32 Wistar rats were analyzed in an early PAH group (n = 8), controls time-paired (n = 8), an end-stage PAH group (n = 8), and their controls (n = 8). Samples were subjected to histological analyses with immunofluorescence staining, autophagy assessment by western blotting, and evaluation of ubiquitin-dependent proteolysis in the LV by immunoprecipitation of ubiquitinated proteins. Echocardiographic, hemodynamic, and heart morphometric parameters were assessed regularly throughout the experiment. Considerable morphological and hemodynamic remodeling of the LV was observed over the course of PAH. The end-stage PAH was associated with significantly impaired LV systolic function and a decrease in LV mass. The LC3B-II expression in the LV was significantly higher in the end-stage PAH group compared to the early PAH group (p = 0.040). The measured LC3B-II/LC3B-I ratios in the end-stage PAH group were significantly elevated compared to the controls (p = 0.039). Immunofluorescence staining showed a significant increase in the abundance of LC3 puncta in the end-stage PAH group compared to the matched controls. There were no statistically significant differences in the levels of expression of all ubiquitinated proteins when comparing both PAH groups and matched controls. Autophagy may be considered as the mechanism behind the LV mass loss at the end stage of PAH.
Topics: Animals; Autophagy; Ubiquitin; Heart Ventricles; Rats, Wistar; Proteolysis; Rats; Male; Pulmonary Arterial Hypertension; Disease Models, Animal; Myocardium; Echocardiography; Hypertension, Pulmonary; Ventricular Remodeling
PubMed: 38956194
DOI: 10.1038/s41598-024-64950-4 -
Scientific Reports Jul 2024This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion...
This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.
Topics: Ferroptosis; Animals; PPAR alpha; Myocardial Reperfusion Injury; 14-3-3 Proteins; Mice; Male; Reactive Oxygen Species; Up-Regulation; Mitochondria; Cell Line; Myocytes, Cardiac; Mice, Inbred C57BL; Rats; Disease Models, Animal
PubMed: 38956068
DOI: 10.1038/s41598-024-64638-9 -
Nature Communications Jul 2024Long-term treatment of myocardial infarction is challenging despite medical advances. Tissue engineering shows promise for MI repair, but implantation complexity and...
Long-term treatment of myocardial infarction is challenging despite medical advances. Tissue engineering shows promise for MI repair, but implantation complexity and uncertain outcomes pose obstacles. microRNAs regulate genes involved in apoptosis, angiogenesis, and myocardial contraction, making them valuable for long-term repair. In this study, we find downregulated miR-199a-5p expression in MI. Intramyocardial injection of miR-199a-5p into the infarcted region of male rats revealed its dual protective effects on the heart. Specifically, miR-199a-5p targets AGTR1, diminishing early oxidative damage post-myocardial infarction, and MARK4, which influences long-term myocardial contractility and enhances cardiac function. To deliver miR-199a-5p efficiently and specifically to ischemic myocardial tissue, we use CSTSMLKAC peptide to construct P-MSN/miR199a-5p nanoparticles. Intravenous administration of these nanoparticles reduces myocardial injury and protects cardiac function. Our findings demonstrate the effectiveness of P-MSN/miR199a-5p nanoparticles in repairing MI through enhanced contraction and anti-apoptosis. miR199a-5p holds significant therapeutic potential for long-term repair of myocardial infarction.
Topics: MicroRNAs; Animals; Myocardial Infarction; Male; Rats; Nanoparticles; Rats, Sprague-Dawley; Apoptosis; Myocardium; Disease Models, Animal; Myocardial Contraction; Administration, Intravenous; Myocardial Ischemia
PubMed: 38956062
DOI: 10.1038/s41467-024-49901-x