Dataset Information

Targeting inflammation and metabolism in hypertrophic cardiomyopathy

ABSTRACT: Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes that code for the structural proteins of the sarcomere, is the most common inherited heart disease. HCM is associated with progressive myocardial hypertrophy and fibrosis, ventricular dysfunction, and arrhythmias. Disease onset during childhood and adolescence carries the risk of morbidity and sudden cardiac death. This study evaluates the impact of pioglitazone on the proteome of myocardial tissue using the α-MHC719/+ HCM mouse model.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Thomas Fröhlich

LAB HEAD: Thomas Fröhlich

PROVIDER: PXD067090 | Pride | 2026-06-29

REPOSITORIES: Pride

ACCESS DATA

Publications

Targeting Inflammation by Pioglitazone and its R-Enantiomer Mitigates Pathological Myocardial Remodeling in Murine Hypertrophic Cardiomyopathy.

Pfaller Anna-Theresa AT Veneziano Claudia C Murthi Sarala Raj SR Stöckl Jan B JB Shashikadze Bachuki B Flenkenthaler Florian F Gorham Josh J Moretti Alessandra A Kitanovic Ana A Gearing Linden J LJ Heinrich Frederik F Durek Pawel P Lehmann Katrin K Mashreghi Mir-Farzin MF Ewert Peter P Fröhlich Thomas T Schmitt Joachim P JP Spielmann Nadine N Hrabě de Angelis Martin M Schmid Manuel M Toepfer Christopher N CN Latz Eicke E Klingel Karin K Santamaria Gianluca G Seidman Jonathan G JG Seidman Christine E CE Wolf Cordula M CM

JACC. Basic to translational science 20260612 7

Hypertrophic cardiomyopathy (HCM) is driven by sarcomeric mutations that cause energetic failure and secondary inflammation. This study demonstrates that targeting this metabolic-inflammatory axis with pioglitazone or its peroxisome proliferator-activated receptor gamma inactive enantiomer, R-pioglitazone, reverses disease progression in a murine HCM model. Both agents restored mitochondrial function (including Mitochondrial Pyruvate Carrier 1 [MPC1] levels) and resolved inflammation. Notably, R ...[more]

PMID: 42287760

Similar Datasets

Project description:Background: Hypertrophic cardiomyopathy (HCM) has traditionally been regarded as a disease of the sarcomere, however it is in the midst of a paradigm shift with growing recognition of contributions beyond the sarcomere to the heterogeneity of HCM phenotypes. Innovative approaches are essential to uncover novel determinants and mechanisms underlying this heterogeneity. Top-down proteomics has emerged as a powerful method for analysis of proteoforms the myriad protein products arising from genetic variants, post-translational modifications (PTMs), and splicing isoforms from a single gene offering a more precise lens to understand the disease heterogeneity in HCM. Yet, how proteoforms are altered on the global scale in HCM has not been investigated. Methods: Global top-down proteomics was performed on myocardial samples from patients with advanced obstructive HCM and nonfailing controls. Specifically, serial protein extraction enabled by the photocleavable surfactant, Azo was employed to solubilize diverse categories of proteins from minimal tissue, including membrane proteins. Subsequently, high-sensitivity top-down mass spectrometry was utilized to detect and quantify proteoforms across various cellular compartments. Results: Using this global top-down approach, we detected ~2000 proteoforms across disparate cellular compartments, including the sarcoplasmic reticulum (SR), cytoskeleton, mitochondria, and nucleus, in advanced obstructive HCM tissues compared to non-failing controls. Quantitative analysis uncovered significant alterations not only in sarcomeric but also cytoskeletal, mitochondrial, nucleosome, and SR proteoforms. Notably, we discovered a significant proteoform crosstalk among the sarcomere, SR, and cytoskeleton. Moreover, we identified a previously unrecognized decrease in succinylated mitochondrial proteoforms as a critical feature of advanced obstructive HCM proteoform landscape, alongside a marked reduction in acetylation of nucleosome proteins. Conclusions: This study represents the most comprehensive analysis of proteoform landscape in HCM to date. We have identified broad proteoform alterations spanning multiple cellular compartments in advanced obstructive HCM, indicating that a complex network of perturbations underlie HCM. These findings highlight pathways beyond the sarcomere that may contribute to HCM pathophysiology, offering potential targets for development of therapeutic interventions.

Project description:Rationale There is a need for new and better biomarkers for hypertrophic cardiomyopathy (HCM) which correlate more closely with disease progression as determined by clinical imaging and biohumoral information. We have used a combination of heart tissue and plasma proteomics to identify potential biomarkers for HCM and developed them into an exploratory targeted proteomic assay. Objective To identify informative staging biomarkers for HCM and develop them into a blood test. The test using 10 µl of plasma, was developed into a 10 min liquid chromatography-tandem/mass spectrometry (LC-MS/MS) assay to analyze multiple candidate biomarkers and evaluate their association with clinical phenotypes in patients with HCM. Methods and Results Myocardial tissue and plasma samples from patients with HCM and healthy volunteers (controls) were screened using a combined gel- and nano-LC quadrupole time of flight MS approach. Twenty-six potential biomarkers were identified from the proteomics screens and developed into a multiplexed targeted proteomic assay. Their association with clinical phenotypes was tested in plasma samples collected from 207 prospectively recruited participants: 110 patients with HCM (50.1 ± 15.0 years, 70% male; 48 [44%] with identified genetic mutations) and 97 controls (49.6 ± 13.4 years, 58% male), randomly split into training (80 HCM, 67 controls) and validation datasets (30 HCM, 30 controls). Six markers (Aldolase Fructose-Bisphosphate A, Complement C3, Glutathione S-Transferase Omega 1, Ras Suppressor Protein 1, Talin 1, and Thrombospondin 1) were significantly increased (P<0.006) in the plasma of HCM patients compared to controls in the training dataset. These markers correlated with left ventricular (LV) wall thickness, LV mass and % myocardial scar on cardiovascular magnetic resonance imaging. Using supervized machine learning (ML) this panel differentiated HCM from controls (area under the curve: 0.89 in the training dataset, sensitivity 96%, 95% confidence interval [CI] 77–93; specificity 87%, 95%CI 77–94; and 0.87 in the validation dataset, sensitivity 97%, 95%CI 83–100; specificity 77%, 95%CI 58–90). Four of the biomarkers as well as the composite ML score of the plasma proteome correlated with the presence of nonsustained ventricular tachycardia and the estimated 5-year risk of sudden cardiac death. Conclusion By developing a high-throughput, multiplex, and targeted proteomic plasma assay we identified 6 biomarkers that correlate with the presence of disease and with clinical risk score for sudden cardiac death.

Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

			Action	DRS
	104.raw	Raw
	105.raw	Raw
	170.raw	Raw
	212.raw	Raw
	222.raw	Raw

Dataset Information

Targeting inflammation and metabolism in hypertrophic cardiomyopathy

Dataset's files

Publications

Targeting Inflammation by Pioglitazone and its R-Enantiomer Mitigates Pathological Myocardial Remodeling in Murine Hypertrophic Cardiomyopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets