Dataset Information

Exercise training decreases the load and changes the content of circulating SDS-resistant protein aggregates in patients with heart failure with reduced ejection fraction

ABSTRACT: Heart failure (HF) is often associated with the deterioration of the protein quality control (PQC) system and the accumulation of protein aggregates. Evidence from tissue biopsies showed that exercise restores PQC system in HF; however, little is known about its effects on plasma proteostasis. Our study aimed to determine the effects of exercise training on the load and composition of plasma SDS-resistant protein aggregates (SRA) in patients with HF with reduced ejection fraction (HFrEF). To accomplish this goal, the load and content of circulating SRA were assessed using D2D SDS-PAGE and mass spectrometry. The exercise program decreased the plasma SRA load in patients with HFrEF. SRA were composed of 31 proteins, with the extracellular chaperones α-2-macroglobulin and haptoglobin as the most abundant ones. 5 patients with HFrEF were enrolled in a 12-week combined (aerobic plus resistance) exercise program with 2 training sessions per week, for a total of 24 sessions. The inclusion criteria included patients aged ≥ 18 years with a diagnosis of HFrEF according to the criteria of the European Society of Cardiology, clinical stability, optimal medical treatment for ≥6 weeks, and patients able to follow the exercise prescription. Exclusion criteria: patients who have undertaken cardiac rehabilitation within the past 12 months; implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT), or combined CRT/ICD device implanted in the last 6 weeks; myocardial infarction in the last 3 months; ischaemia signs during cardiopulmonary exercise testing; symptomatic and/or exercise-induced cardiac arrhythmia or conduction disturbances; currently pregnant or intend to become pregnant in the next year; inability to exercise or conditions that may interfere with exercise intervention; expectation of receiving a cardiac transplant in the next 6 months; participation in another clinical trial; patients who are unable to understand the study information or complete the questionnaires.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

DISEASE(S): Heart Failure

SUBMITTER: Rui Vitorino

LAB HEAD: Fernando Ribeiro

PROVIDER: PXD045161 | Pride | 2025-05-06

REPOSITORIES: Pride

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Exercise training decreases the load and changes the content of circulating SDS-resistant protein aggregates in patients with heart failure with reduced ejection fraction.

Gouveia Marisol M Schmidt Cristine C Basilio Priscilla Gois PG Aveiro Susana S SS Domingues Pedro P Xia Ke K Colón Wilfredo W Vitorino Rui R Ferreira Rita R Santos Mário M Vieira Sandra I SI Ribeiro Fernando F

Molecular and cellular biochemistry 20231030 10

<h4>Background</h4>Heart failure (HF) often disrupts the protein quality control (PQC) system leading to protein aggregate accumulation. Evidence from tissue biopsies showed that exercise restores PQC system in HF; however, little is known about its effects on plasma proteostasis.<h4>Aim</h4>To determine the effects of exercise training on the load and composition of plasma SDS-resistant protein aggregates (SRA) in patients with HF with reduced ejection fraction (HFrEF).<h4>Methods</h4>Eighteen ...[more]

PMID: 37902886

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Project description:Aims: In humans, secretome of pericardial (PAT) and epicardial adipose tissue (EAT) contribute to establishment of heart failure (HF) with preserved ejection fraction (HFpEF) originating from pressure-overload due to metabolic disorder. We examined whether PAT affects also manifestation and progression of pressure-induced HF in the absence of metabolic burden in mice. Methods and results: Progressive remodelling was assessed in C57BL/6J males, aged 9 wks, randomly assigned to sham surgery or transverse aortic constriction (TAC) for 1 week (early pressure-overload), 8 (chronic pressure-overload), or 12 weeks (HFrEF) with or without concomitant PAT excision. PAT removal did not affect early (1 wk TAC), and chronic (8 wks) pressure-overload induced concentric remodelling. However, the initial PAT excision prevented TAC-induced expansion of pro-inflammatory macrophages during early pressure-overload and attenuated the persistent LV expression of pro-hypertrophic, pro-inflammatory and pro-fibrotic factors as well as the drastic LV dilation and progressive systolic dysfunction in the long-term and thereby protected against the transition to HFrEF. This protection was associated with significant reduction of microscar and perivascular fibrosis. The latter was, at least in part, attributed to reduced accumulation of pro-fibrotic CD206+ macrophages around the coronaries 12 wks post-surgery in the absence of PAT compared to mice with intact PAT. In addition, PAT bulk RNA sequencing revealed the initiation of an extracellular matrix deposition programme in the PAT early upon TAC surgery, which might trigger fibrotic responses in the underlying myocardium. Indeed, isolated naive adult cardiac fibroblasts exposed to PAT lysate from 12 wks TAC mice increased collagen production and cell viability/proliferation. Conclusion: Our data suggest PAT to play divergent roles in the chronically pressure overloaded heart versus HFrEF - while widely not affecting concentric hypertrophy, PAT removal counteracts manifestation of HFrEF in mice, at least in part, by preventing excessive fibrotic and macrophage responses.

Project description:<p><strong>OBJECTIVE:</strong> To explore the cardioprotective effects of exercise-derived β-aminoisobutyric (BAIBA) on cardiomyocyte apoptosis and energy metabolism in a rat model of heart failure (HF).</p><p><strong>METHODS:</strong> In male Sprague-Dawley rats (8-week-old), myocardial infarction (MI) was used to induce HF by ligating the left anterior descending branch of the coronary artery. In the Sham group, the coronary artery was threaded but not ligated. After HF development, Sham and HF rats were exercised 60 min daily, 5 days per week on a treadmill for 8 weeks (50-60% maximal intensity) and exercise-induced cardiac remodeling after MI were assessed using echocardiography, hematoxylin and eosin (H&E), Masson’s Trichrome and TUNEL staining for the detection of apoptosis-associated factors in cardiac tissue. High-throughput sequencing and mass spectrometry were used to measure BAIBA production and to explore its cardioprotective effects and molecular actions. To further characterize the cardioprotective effects of BAIBA, an <em>in vitro</em> model of apoptosis was generated by applying H2O2 to H9C2 cells to induce mitochondrial dysfunction. In addition, cells were transfected with either a miR-208b analogue or a miR-208b inhibitor. Apoptosis-related proteins were detected by Western Blotting (WB). ATP production was also assessed by luminometry. After administration of BAIBA and Compound C, the expression of proteins related to apoptosis, mitochondrial function, lipid uptake and β-oxidative were determined. Changes in the levels of reactive oxygen species (ROS) were assessed by fluorescence microscopy. In addition, alterations in membrane potential (δψm) were obtained by confocal microscopy.</p><p><strong>RESULTS:</strong> Rats with HF after MI are accompanied by mitochondrial dysfunction, metabolic stress and apoptosis. Reduced expression of apoptosis-related proteins was observed, together with increased ATP production and reduced mitochondrial dysfunction in the exercised compared with the Sham (non-exercised) HF group. Importantly, exercise increased the production of BAIBA, irrespective of the presence of HF. To assess whether BAIBA had similar effects to exercise in ameliorating HF-induced adverse cardiac remodeling, rats were treated with 75 mg/kg/day of BAIBA and we found BAIBA had a similar cardioprotective effect. Transcriptomic analyses found that the expression of miR-208b was increased after BAIBA administration, and subsequent transfection with an miR-208b analogue ameliorated both the expression of apoptosis-related proteins and energy metabolism in H2O2-treated H9C2 cells. In combining transcriptomic with metabolomic analyses, we identified AMPK as a downstream target for BAIBA in attenuating metabolic stress in HF. Further cell experiments confirmed that BAIBA increased AMPK phosphorylation and had a cardioprotective effect on downstream fatty acid uptake, oxidative efficiency and mitochondrial function, which was prevented by the AMPK inhibitor Compound C.</p><p><strong>CONCLUSION: </strong>Exercise-generated BAIBA can reduce cardiomyocyte metabolic stress and apoptosis induced by mitochondrial dysfunction through the miR-208b/AMPK pathway.</p>

Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus inﬂuencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.

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	D2D_exercise_MS_summary.xlsx	Xlsx
	ET10A.raw	Raw
	ET10B.raw	Raw
	ET11A.raw	Raw
	ET11B.raw	Raw