Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion.
Ontology highlight
ABSTRACT:
SUBMITTER: Lisewski U
PROVIDER: S-EPMC8638375 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Introduction: The ribosomal protein L3-like (RPL3L) is a heart and skeletal muscle-specific ribosomal protein and paralogue of the more ubiquitously expressed RPL3 protein. Mutations in the human RPL3L gene are linked to childhood cardiomyopathy and age-related atrial fibrillation, yet the function of RPL3L in the mammalian heart remains unknown. Methods and Results: Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults. Rpl3l gene-deleted mice were generated to examine the role of this gene in the heart, although Rpl3l -/- mice showed no overt changes in cardiac structure or function at baseline or after pressure overload hypertrophy, likely because RPL3 expression was upregulated and maintained in adulthood. mRNA expression analysis and ribosome profiling failed to show differences between the hearts of Rpl3l null and wild type mice in adulthood. Moreover, ribosomes lacking RPL3L showed no differences in localization within cardiomyocytes compared to wild type controls, nor was there an alteration in cardiac tissue ultrastructure or mitochondrial function in adult Rpl3l -/- mice. Similarly, overexpression of either RPL3 or RPL3L with adeno-associated virus -9 in the hearts of mice did not cause discernable pathology. However, by 18 months of age Rpl3l -/- null mice had significantly smaller hearts compared to wild type littermates. Conclusion: Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight.
| S-EPMC9886673 | biostudies-literature
Project description:Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and protects cardiac LDH exposed to HPS produced by the contracting heart. Male, Sprague-Dawley and Spontaneously-Hypertensive-Heart-Failure (SHHF) rats were treated orally with either water (control) or TMAO. In vitro, LDH with or without TMAO was exposed to HPS and was evaluated using fluorescence correlation spectroscopy. TMAO-treated rats showed higher diuresis and natriuresis, lower arterial pressure and plasma NT-proBNP. Survival in SHHF-control was 66% vs 100% in SHHF-TMAO. In vitro, exposure of LDH to HPS with or without TMAO did not affect protein structure. In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure.
| S-EPMC7334024 | biostudies-literature
Project description:BACKGROUND Many heart failure (HF) cases are caused by idiopathic dilated cardiomyopathy (iDCM). This study explored the mechanisms of the development and progression of HF caused by iDCM. MATERIAL AND METHODS The gene expression profiles of 102 samples were downloaded from the GEO database (GSE5406). Differentially expressed genes (DEGs) were identified through GO analysis and a KEGG pathway analysis, respectively. A protein-protein interaction (PPI) network was constructed and analyzed to screen potential regulatory proteins. In addition, MCODE and a cytoHubba plugin were used to identify the module and hub genes of DEGs. Finally, transcription factors (TFs) were predicted using PASTAA. We did not perform whole-exome sequencing (WES) for detecting mitochondrial DNA (mtDNA). RESULTS A total of 197 DEGs were screened, and 3 modules, and 4 upregulated and 11 downregulated hub genes were screened. The GO analysis focused on the terms and 12 KEGG pathways were enriched. The FOS, TIMP1, and SERPINE1 hub genes, as well as some key TFs, demonstrated important roles in the progression of HF caused by iDCM. CEBPD, CEBOB, CDC37L1, and SRGN may be new targets for HF in iDCM patients. CONCLUSIONS The identified DEGs and their enriched pathways provide references for exploring the mechanisms of the development and progression of HF patients with iDCM. Moreover, modules, hub genes, and TFs may be useful in the treatment and diagnosis of HF patients with iDCM. However, mtDNA was not investigated.
| S-EPMC6216482 | biostudies-literature
Project description:Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T(4) before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.
| S-EPMC2790327 | biostudies-literature
Project description:Patients with heart failure (HF) syndromes have been categorized as those with reduced ejection fraction (EF) or preserved EF (HFpEF), and ischemia plays a key role in both types. HF remains a major cause of morbidity and mortality worldwide, and with the aging of our population this burden continues to rise, predominantly as a result of hospitalizations for HFpEF. Patients with obstructive coronary artery disease more likely have HF with reduced EF, rather than HFpEF, secondary to acute ischemic injury resulting in myocardial infarction, and large outcomes trials of treatments with neurohumoral inhibition have documented reduced adverse outcomes. In contrast, similar treatments in patients with HFpEF have not proven beneficial. This therapeutic dilemma may be attributed, in part, to heterogeneity in the underlying pathophysiology with different systemic and myocardial signaling pathways, despite similar clinical presentations and findings, in patients with HFpEF. Also, emerging evidence indicates that impaired myocardial perfusion and inflammation secondary to multiple comorbidities are key mechanisms in HFpEF. We will thoroughly review the role of ischemic heart disease in the pathogenesis of HF with reduced EF and HFpEF, and discuss the medical management strategies available for these conditions.
| S-EPMC6534154 | biostudies-literature
Project description:BackgroundSudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.Methods and resultsUsing whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.ConclusionsDisruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.
| S-EPMC4917016 | biostudies-literature
Project description:The KCNE2 gene encodes a single transmembrane domain protein that modulates a variety of K+ channel functions in various tissues. Here we show that cardiac KCNE2 transcript levels are approximately 10-fold upregulated at the end of pregnancy. This upregulation was mimicked by 17-beta estradiol but not by 5alpha-dihydrotestosterone treatments in ovariectomized mice. To investigate the mechanism of KCNE2 transcriptional regulation by estrogen, we experimentally identified KCNE2 transcription start sites, delineated its gene structure and characterized its promoter region. Estrogen treatment stimulated KCNE2 promoter activity in a dose-dependent manner and ICI 182,780 blocked estrogen stimulation. A direct genomic mechanism was demonstrated by (i) the loss of estrogen responsiveness in the presence of a DNA-binding domain mutant estrogen receptor alpha or mutant KCNE2 ERE and (ii) binding of ERalpha to the KCNE2 ERE. These findings show that a genomic mechanism of estrogen action alters KCNE2 expression, which may have important physiological implications.
| S-EPMC2893227 | biostudies-literature
Project description:Background Follow-up in a nurse-led heart failure ( HF ) clinic is recommended in HF guidelines, but its association with outcomes remains controversial, with previous studies including few and highly selected patients. Thus, large analyses of "real-world" samples are needed. Aims were to assess: (1) independent predictors of and (2) prognosis associated with planned referral to nurse-led HF clinics. Methods and Results We analyzed data from the SwedeHF (Swedish HF Registry) using multivariable logistic regressions to identify independent predictors of planned referral to a nurse-led HF clinic and multivariable Cox regressions to test associations between planned referral and outcomes (all-cause death, HF hospitalization, and their composite). Of 40 992 patients, 39% were planned to be referred to a follow-up in a nurse-led HF clinic. Independent characteristics associated with planned referral were shorter duration of HF , clinical markers of more-severe HF, such as lower ejection fraction, higher New York Heart Association class and N-terminal pro-B-type natriuretic peptide, and lower blood pressure, as well as cohabitating versus living alone, male sex, fewer comorbidities, and more use of HF treatments. After adjustments, planned referral to a nurse-led HF clinic was associated with reduced mortality and mortality/ HF hospitalization, but not HF hospitalization alone. Conclusions In this nation-wide registry, 39% of our identified HF cohort was planned to be referred to a nurse-led HF clinic. Planned referral reflected more-severe HF , but also sex- and family-related factors, and it was independently associated with lower risk of death, but not of HF hospitalization.
| S-EPMC6585319 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis.
| S-EPMC4794722 | biostudies-literature
Project description:Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.
| S-EPMC2542870 | biostudies-other