Thrombospondin 1 Aggravates the Progression of Heart Failure with Preserved Ejection Fraction by Inhibiting Mitophagy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305470 | GEO | 2025/12/30
REPOSITORIES: GEO
Similar Datasets
Project description:Heart failure with preserved ejection fraction (HFpEF) is characterised by a distinct but poorly understood in skeletal muscle pathology. In a rat model ZSF1, we identify impaired myonuclear accretion as a mechanism for ablated myofiber growth in HFpEF following resistance exercise intervention. Muscle vascular or mitochondrial dysfunction, or impaired protein synthesis signalling, do not appear as primary limiting mechanisms, and cardiac therapies do not attenuate skeletal muscle pathology. However, we identify that acute caloric restriction rejuvenates myofiber growth in HFpEF during resistance exercise intervention.
2025-01-19 | E-MTAB-12494 | biostudies-arrayexpress
Project description:<p>Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, the role of protein acetylation in cardiac metabolic impairments during the pathogenesis of HFpEF remains insufficiently investigated. In this study, a two-hit strategy, involving a high-fat diet and Nω-nitro-L-arginine methyl ester (L-NAME), was employed to induce the HFpEF model in mice. Significant cardiac diastolic dysfunction, pathological remodeling, and enhanced protein hyperacetylation were observed in the hearts of the two-hit HFpEF mice. Acetylome profiling revealed that the hyperacetylated proteins were predominantly localized to mitochondria and enriched in metabolic pathways, particularly in fatty acid oxidation (FAO). Furthermore, the HFpEF heart exhibited reduced FAO capacity and abnormal lipid accumulation. Activation of mitochondrial protein deacetylation restored FAO capacity and alleviated cardiac dysfunction in the HFpEF heart, whereas inhibition of mitochondrial deacetylase directly induced lipid metabolism disorders in cardiomyocytes. Notably, we identified Dlat, a pyruvate metabolism enzyme, as the key transacetylase responsible for mitochondrial protein hyperacetylation in the HFpEF heart. Overexpression of Dlat enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, thereby inducing pathological changes resembling the HFpEF phenotype. In contrast, Dlat knockdown effectively mitigated FAO inhibition and functional impairment in the two-hit HFpEF mice. Through discovery-driven approaches, we demonstrated that Dlat directly binds to the alpha subunit of mitochondrial trifunctional protein (HADHA) and triggers its acetylation at the K728 site, thereby inactivating HADHA enzymatic activity. Reactivating HADHA, either by cardiac-specific HADHA overexpression or oral administration of a biogenic polyamine, restored cardiac FAO capacity and prevented the development of HFpEF. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and the development of HFpEF. Activation of mitochondrial deacetylase or enhancement of cardiac FAO capacity may offer novel strategies for restoring cardiac metabolic homeostasis and function in HFpEF.</p>
2025-09-01 | MTBLS12919 | MetaboLights
Project description:In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1 month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.
2021-09-01 | GSE181184 | GEO
Project description:Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Klf9 is dysregulated in human and rodent cardiomyopathy. Young adult global Klf9-knockout mice displayed hypertrophic cardiomyopathy that was characterized by depressed systolic function, increased left ventricular mass and pulmonary congestion. Klf9 knockout led to mitochondrial disarray and fragmentation in cardiomyocytes. Biochemical analysis confirmed that mitochondrial respiratory function was impaired in Klf9-knockout cardiomyocytes, with reduced myocardial ATP levels and elevated ROS. Furthermore, cardiac-specific Klf9-deficient mice phenocopied global Klf9-knockout mice, suggesting that cardiac Klf9 is essential for mitochondrial homeostasis and heart function. Moreover, cardiac Klf9 deficiency inhibited mitophagy induced by angiotensin II (ANGII), thereby leading to accumulation of dysfunctional mitochondria and acceleration of heart failure in mice in response to ANGII treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function via promoting mitophagy in mice in response to ANGII treatment. Molecular mechanism studies indicated that Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2 by directly binding to its promoter region, thereby regulating mitochondrial dynamics and mitophagy. Finally, we performed Mfn2 rescue experiments in Klf9-CKO mice and found that AAV-mediated Mfn2 rescue in heart improved cardiac mitochondrial and systolic function in Klf9-CKO mice treated with or without ANGII. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
2024-10-03 | GSE278326 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodeling. Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. CITE-Seq analysis of cardiac immune cells reveals an altered abundance and/or transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including upregulation of Trem2, which was also recently implicated in obesity and atherosclerosis. The role of macrophage Trem2 in cardiac remodeling, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls, and Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programs. Furthermore, we found that plasma levels of soluble TREM2 are elevated in human heart failure. Together, our data suggest a novel cardioprotective role for macrophage Trem2 in cardiac remodeling and heart failure and provide an atlas for the identification of additional targets that can lead to improved diagnostic and therapeutic strategies for HFpEF.
2023-05-01 | GSE211166 | GEO
Project description:Heart failure affects 2–3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics will show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction ≥ 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group. <br> Sequencing data from clinical patients fall under GDPR regulations of sharing of personal data and will be made available through EGA-SE.
2019-03-02 | E-MTAB-7454 | biostudies-arrayexpress
Project description:Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, evidence-based therapies for HFpEF are rare, likely due to an incomplete understanding of this disease. This study sought to identify the cardiac-specific features of protein and phosphoprotein in a murine model of HFpEF using mass spectrometry. HFpEF mice developed moderate hypertension, left ventricle (LV) hypertrophy, lung congestion and diastolic dysfunction. Proteomics analysis of the LV tissue showed that 897 proteins were differentially expressed between HFpEF and Sham mice. We observed abundant changes in sarcomeric proteins, mitochondrial-related proteins, and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Upregulated pathways by GSEA analysis were related to immune modulation and muscle contraction, while downregulated pathways were predominantly related mitochondrial metabolism. Western blot analysis validated SIRT3 downregulated cardiac expression in HFpEF. Phosphoproteomics analysis showed that 72 phosphopeptides were differentially regulated between HFpEF and sham LV. Aberrant phosphorylation patterns mostly occurred in sarcomere proteins and nuclear-localized proteins associated with contractile dysfunction and cardiac hypertrophy. Seven aberrant phospho-sites were observed at the z disk binding region of titin. While total titin cardiac expression remained unaltered, its stiffer N2B isoform was significantly increased in HFpEF. Thus, these results show profound changes in proteins related to mitochondrial metabolism and function and the cardiac contractile apparatus in HFpEF. We propose that SIRT3 plays a key role and may be a target for drug development in HFpEF.
2022-10-15 | PXD033501 | Pride
Project description:BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients. Clinically, HFpEF prevalence show age and gender biases. Although the majority of HFpEF patients are elderly, there is an emergence of young HFpEF patients. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. METHODS AND RESULTS: HFpEF dietary regimen (HFD + L-NAME) was used to induce HFpEF in wildtype and telomerase RNA knockout mice (mTRG2 and mTRG3), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in mTRG2 (at 6-weeks) and mTRG3 (at 4-weeks) compared to wildtype (8-weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that p53 is necessary for the development of HFpEF. CONCLUSIONS: Here we demonstrate that p53 activation is critical for the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 prevents HFpEF upon HFD + L-NAME challenge.
2022-07-06 | GSE195482 | GEO
Project description:Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, the role of protein acetylation in cardiac metabolic impairments during the pathogenesis of HFpEF remains insufficiently investigated. In this study, a two-hit strategy, involving a high-fat diet and Nω-nitro-L-arginine methyl ester (L-NAME), was employed to induce the HFpEF model in mice. Significant cardiac diastolic dysfunction, pathological remodeling, and enhanced protein hyperacetylation were observed in the hearts of the two-hit HFpEF mice. Acetylome profiling revealed that the hyperacetylated proteins were predominantly localized to mitochondria and enriched in metabolic pathways, particularly in fatty acid oxidation (FAO). Furthermore, the HFpEF heart exhibited reduced FAO capacity and abnormal lipid accumulation. Activation of mitochondrial protein deacetylation restored FAO capacity and alleviated cardiac dysfunction in the HFpEF heart, whereas inhibition of mitochondrial deacetylase directly induced lipid metabolism disorders in cardiomyocytes. Notably, we identified Dlat, a pyruvate metabolism enzyme, as the key transacetylase responsible for mitochondrial protein hyperacetylation in the HFpEF heart. Overexpression of Dlat enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, thereby inducing pathological changes resembling the HFpEF phenotype. In contrast, Dlat knockdown effectively mitigated FAO inhibition and functional impairment in the two-hit HFpEF mice. Through discovery-driven approaches, we demonstrated that Dlat directly binds to the alpha subunit of mitochondrial trifunctional protein (HADHA) and triggers its acetylation at the K728 site, thereby inactivating HADHA enzymatic activity. Reactivating HADHA, either by cardiac-specific HADHA overexpression or oral administration of a biogenic polyamine, restored cardiac FAO capacity and prevented the development of HFpEF. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and the development of HFpEF. Activation of mitochondrial deacetylase or enhancement of cardiac FAO capacity may offer novel strategies for restoring cardiac metabolic homeostasis and function in HFpEF.
2025-09-11 | PXD068270 |
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO