Biology subjects

Tollison, W.

Publications and source records attributed to Tollison, W..

6 recordsLinked to original sources

bioRxiv2026

Multimodality Molecular Profiling Nominates Targetable Mechanisms in Progressive RV Dysfunction

BackgroundRight ventricular dysfunction (RVD) is a robust predictor of mortality in multiple cardiovascular diseases. Currently, it remains unclear whether the severity of RVD corresponds to distinct cellular and molecular alterations, and this has important implications for defining optimal therapeutic targets. To address this knowledge gap, we performed a multi-omics evaluation of pulmonary artery banded (PAB) pigs with differing degrees of RV compromise. MethodsPAB pigs were stratified into mild and severe RVD groups using an RV ejection fraction cutoff of 35%. RV tissue from control, mild RVD, and severe RVD animals was analyzed using single-nucleus RNA sequencing, mitochondrial and cytoplasmic proteomics, and phosphoproteomics. Histological analyses corroborated multi-omic findings. ResultsCardiac MRI revealed progressive structural and functional alterations in mild and severe RVD pigs. snRNAseq demonstrated that advancing RVD was associated with loss of cardiomyocytes, accumulation of efferocytosis-impaired macrophages, and dysregulated endothelial cells and pericytes. Combined transcriptomic and proteomic analyses showed escalating impairments of complex cardiomyocyte metabolism with worsening RVD. RV microvasculature was compromised with severe RVD as there were alterations in endothelial cell/pericyte genetic regulation, co-localization patterns in RV sections, and ectopic cardiomyocyte HIF1 expression. Analysis of both mitochondrial and global proteostasis revealed greater compromise in mitochondrial proteostasis, including downregulation of mitochondrial proteases, chaperones, and ribosomes. Paradoxically, cytoplasmic ribosomes were upregulated in severe RVD. The predicted kinome and phosphatome were uniquely altered in mild RVD as compared to severe RVD. Finally, integration of multi-omic approaches identified insufficient mitochondrial unfolded protein response, impaired macrophage efferocytosis, and activation of the ribotoxic stress response as potential contributors to severe RVD. ConclusionsOur multi-omic analysis defines the cellular and molecular landscape of progressive RVD and nominates druggable pathways that may promote progressive RV dysfunction. Future studies are needed to determine how targeting these pathways influences RV phenotypes.

physiology↗

bioRxiv2026

Proteomics Defines Shared and Divergent Alterations in the Right Atrium and Right Ventricle in Porcine Right Heart Failure

Right heart failure is due to both right atrial and right ventricular dysfunction. While the two chambers are distinct, the proteomic response to pressure overload is undefined. Here, we used quantitative proteomics to evaluate changes in both chambers in pulmonary artery banded pigs. We found common alterations in oxidative phosphorylation, ribosome regulation, integrin-mediated adhesion, and glycolysis enzymes. However, the right atrium had more pronounced deficits in the TCA cycle and branched chain amino acid metabolism. Thus, these data highlight metabolic pathways that could be evaluated to selectively enhance right atrial function.

biochemistry↗

bioRxiv2025

Multi-omic Evaluations Nominate an ER-Mitochondrial Axis and Inflammatory Macrophage as Drivers of Right Atrial Dysfunction

BackgroundRight atrial (RA) dysfunction is an emerging risk factor for poor outcomes in pulmonary arterial hypertension, however the mechanisms underlying compromised RA function are understudied. ObjectivesMulti-omic analyses defined the cellular and molecular mediators associated with RA dysfunction in pulmonary artery banded (PAB) swine. Methods4-week-old castrated male Yorkshire pigs were subjected to PAB and aged six weeks to induce right heart failure. Cardiac MRI evaluated RA size and function. snRNAseq defined the cell-specific alterations in RA tissue. Mitochondrial proteomics and metabolomics analyses examined the metabolic alterations in RA samples. Inducible pluripotent stem cell-derived atrial cardiomyocytes (iPSC-ACM) were treated with tunicamycin to induce endoplasmic reticulum (ER) stress and mitochondrial structure and function were probed. ResultsPAB induced RA dilation/dysfunction and atrial cardiomyocyte hypertrophy. snRNAseq demonstrated PAB altered the cellular composition of the RA defined by increased inflammatory macrophages and an alteration of cardiomyocyte subpopulations. RA cardiomyocytes exhibited ER stress and mitochondrial metabolic enzyme dysregulation. PAB RAs, but not PAB right ventricles, had downregulation of branched chain amino acid degrading enzymes. Metabolomics profiling revealed BCAA and fatty acid metabolism were impaired in the dysfunctional RA. Tunicamycin-induced ER stress disrupted mitochondrial structure/function in iPSC-ACMs. ConclusionsMulti-omic evaluations demonstrate RA dysfunction is characterized by cardiomyocyte metabolic derangements due to ER dysregulation and an accumulation of pro-inflammatory macrophages.

physiology↗

bioRxiv2025

Glycoprotein 130 Antagonism Counteracts Metabolic and Inflammatory Alterations to Enhance Right Ventricle Function in Pulmonary Artery Banded Pigs

BackgroundRight ventricular dysfunction (RVD) is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of glycoprotein-130 (GP130) signaling with the small molecule SC144 improves RV function in rodent RVD via anti-inflammatory and metabolic mechanisms. However, SC144s efficacy and molecular effects in a translational large animal model of RVD are unknown. Methods4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144, n=5] or vehicle [PAB-Veh, n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac MRI quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue. Quantitative proteomics examined RV mitochondrial protein regulation. ResultsSC144 significantly improved RV ejection fraction (Control: 60{+/-}4%, PAB-Veh: 22{+/-}10%, PAB-SC144: 37{+/-}6%) despite similar RV afterload. Single-nucleus RNA sequencing demonstrated PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared to control, and many of these changes were blunted by SC144. SC144 combatted the downregulation of cardiomyocyte metabolic genes induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 activation. Correspondingly, SC144 rebalanced RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed SC144 restored fatty acid metabolism. Finally, CellChat analysis revealed SC144 restored pericyte-endothelial cell cross-talk. ConclusionGP130 antagonism blunts elevated immune cell abundance, reduces pro-inflammatory gene transcription in macrophages and lymphocytes, rebalances autophagy and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte communication to improve RV function.

physiology↗

bioRxiv2024

Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown. Here, we showed ferrostatin-1 mediated ferroptosis antagonism improve right heart structure and function in pulmonary artery banded pigs. Molecularly, ferrostatin-1 restored mitochondrial cristae structure and combatted downregulation of electron transport chain proteins. Metabolomics and lipidomics analyses revealed ferrostatin-1 improved fatty acid metabolism. Thus, these translational data suggest ferroptosis may be a therapeutic target for RHF. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/590907v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@9c36fforg.highwire.dtl.DTLVardef@1deda21org.highwire.dtl.DTLVardef@1c2e4e1org.highwire.dtl.DTLVardef@409181_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

biochemistry↗