Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA91653 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n=1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.
2021-12-08 | MTBLS3174 | MetaboLights
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-17 | GSE249409 | GEO
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:Gene profiling of pathological cardiac hypertrophy vs physiological hypertrophy
| PRJNA100305 | ENA
Project description:Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure (ChIP-Seq)
| PRJNA376190 | ENA
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-17 | GSE249411 | GEO
Project description:Heart failure is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. Coordinate activation of developmental, inflammatory, fibrotic and growth regulators underlies the hallmark phenotypes of pathologic cardiac hypertrophy and contractile failure. While transactivation in this context is known to be associated with recruitment of histone acetyl-transferase enzymes and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in heart failure. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during the evolution of heart failure. BET inhibition suppresses cardiomyocyte hypertrophy in a cell-autonomous manner, confirmed by RNA interference in vitro. Following both pressure overload and neurohormonal stimulation, BET inhibition potently attenuates pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to heart failure pathogenesis. Specifically, BET bromodomain inhibition in mice abrogates pathology-associated pause release and transcriptional elongation, thereby preventing activation of cardiac transcriptional pathways relevant to the gene expression profile of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in heart failure. ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor
2013-08-06 | E-GEOD-46668 | biostudies-arrayexpress
Project description:Background: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy regresses pre-existing cardiac hypertrophy, and prevents the progression to heart failure. Methods and Results: When male Dahl salt-sensitive (DSS) rats are fed a high salt (HS) diet, all rats develop cardiac hypertrophy after 5 weeks (H). Thereafter, rats were treated with vehicle (V), paricalcitol (PC, an active vitamin D analog at 200ng, IP 3x/wk), enalapril (EP, 90ug/day), and PC+EP. All groups were continued on the HS diet and evaluated after 4 weeks of therapy. The PC and PC+EP, but not the V and EP-only groups, showed significant regression of pre-existing cardiac hypertrophy. The signs of decompensated heart failure were evident in the vehicle-treated group; these heart failure parameters significantly improved with PC, EP or PC+EP therapy. The expression of PKCe, which is regulated by Ca2+ and known to stimulate cardiac hypertrophy, was significantly increased in the vehicle group, and PC, EP or PC+EP effectively decreased PKCe activation. We also observed normalization of genetic alterations during progression to heart failure with PC treatment. Conclusions: PC treatment resulted in both the regression of pre-existing cardiac hypertrophy, and the attenuation of the progression to heart failure, compared to improvement in progression to heart failure by EP alone. These beneficial findings in the heart were associated with inhibition of PKCe activation, and reversal of gene alterations.
2010-09-14 | GSE24110 | GEO