Biology subjects

Mendelson, J. B.

Publications and source records attributed to Mendelson, J. B..

11 recordsLinked to original sources

bioRxiv2026

Multi-Omic Profiling Defines the Renal Mechanisms of Cardiovascular-Kidney-Metabolic Syndrome in Pulmonary Arterial Hypertension

Background: Cardiovascular-kidney-metabolic (CKM) syndrome integrates cardiac, renal, and metabolic abnormalities that drive multi-organ injury. In pulmonary arterial hypertension (PAH), CKM manifests as systemic metabolic derangements, right ventricular dysfunction, and renal compromise. Renal dysfunction strongly predicts mortality in PAH, yet current therapies provide little renal benefit. Moreover, the mechanisms driving PAH nephropathy remain poorly understood, limiting our ability to effectively treat PAH-CKM. Methods: Single-nucleus RNA sequencing identified cell-type-specific transcriptional alterations in autopsy-derived kidneys from control (n=5) and PAH (n=4) patients. Mitochondrial, cytoplasmic, and phosphoproteomic analyses profiled proteomic alterations. AlphaFold 3/ChimeraX modeling defined the predicted structural consequences of altered protein phosphorylation. Histological analysis assessed renal fibrosis, glomerular structure, immune cell infiltration, and nephron segment density. Results: 3 of 4 PAH patients exhibited renal impairment, with a cohort mean estimated glomerular filtration rate of 61 plus or minus 36 mL/min/1.73m squared. snRNA-seq identified a distinct cellular architecture in PAH kidneys, marked by an increase in thick ascending limb, proximal tubule, and immune cell nuclei and depletion of collecting duct nuclei. Transcriptional profiling demonstrated proximal tubule and thick ascending limb cells both upregulated fatty acid oxidation, ferroptosis, and cuproptosis pathways. PAH lymphocytes displayed heightened T87 cell receptor signaling, natural killer cell-mediated cytotoxicity, and Th17 differentiation. Histological analyses demonstrated increased perivascular fibrosis, glomerular T-cell infiltration, and a reduction in glomerular basement membrane density in PAH kidneys. Mitochondrial and cytoplasmic proteomics revealed broad metabolic dysfunction characterized by impaired {beta}-oxidation, TCA cycle activity, amino acid metabolism, transsulfuration, and urea cycle pathways. Phosphoproteomics predicted increased GSK3{beta}, STK, and casein kinase activity in PAH kidneys. Finally, using the totality of our data, we nominated multiple druggable targets that could be evaluated to counteract PAH nephropathy. Conclusions: Integrated multi-omic profiling demonstrates PAH nephropathy is defined by glomerular structural remodeling, proximal nephron ferroptotic and cuproptotic signaling, amino acid metabolic dysregulation, and innate and adaptive leukocyte activation. Future studies intervening on these pathways could lead to the development of novel therapeutics to augment renal function in PAH.

molecular biology↗

bioRxiv2026

Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy

Right ventricular failure (RVF) is a robust predictor of mortality in pulmonary arterial hypertension (PAH); however, the mechanisms linking RVF to end-organ dysfunction remain unclear. Hepatic impairments portend poor outcomes in PAH, but the cell-specific effects of PAH on the human liver are unknown. Here, we performed single nucleus RNA sequencing on autopsy-derived liver tissue from five PAH patients and four non-PAH controls and compared these findings to non-alcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). PAH hepatocytes were characterized by a pro-proliferative, Warburg-like metabolic phenotype. PAH endothelial cells (ECs) also adopted a Warburg-like profile. Although EC PI3K-Akt activation was present in PAH and FALD ECs, only PAH ECs demonstrated impaired adhesion/barrier signaling. In PAH hepatic stellate cells (HSCs), PI3K-Akt signaling was enriched, while NASH and FALD HSCs co-activated PI3K-Akt and TGF-{beta}. Activated HSC abundances were increased in PAH livers and associated with heightened central vein fibrosis. PAH and NASH macrophages showed elevated complement signaling but reduced JAK-STAT activity. PAH livers exhibited dysregulated vasoactive gene expression, increased interleukin-6 expression in HSCs, and suppressed hepatocyte ketone metabolism. Correlational analysis demonstrated that HSC HIF-1 activation was associated with PAH severity. In total, these findings define the metabolic and inflammatory hepatopathy of PAH.

biochemistry↗

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

Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers forPulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance

BackgroundPulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied. MethodsWe evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics/lipidomics of quadriceps (predominately fast fibers) and soleus (predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH. ResultsMCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the quadriceps and soleus muscles of MCT rats. In the quadriceps, there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the soleus. Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the quadriceps only. Mitochondrial proteomics and tissue metabolomics/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the quadriceps had impairments in oxidative phosphorylation/fat metabolism and storage of triacylglycerides. However, the soleus showed signs of proteasome deficiencies and alterations in phosphatidylcholine/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides. ConclusionOur data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.

systems biology↗

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

17β-Estradiol Counteracts Pathological Microtubule Remodeling To Enhance Cardiac Function

The female-predominate sex hormone 17{beta}-estradiol exerts cardioprotective effects via multiple mechanisms. Available data demonstrate 17{beta}-estradiol modulates microtubule dynamics in vitro, but its effects on pathogenic microtubule remodeling in pressure-overloaded cardiomyocytes are unexplored. Here, we show 17{beta}-estradiol directly blunts microtubule polymerization in vitro, counteracts endothelin-mediated microtubule remodeling in iPSC-cardiomyocytes, and mitigates microtubule stabilization in pulmonary artery banded right ventricular cardiomyocytes. 17{beta}-estradiol treatment blunts cardiomyocyte and nuclear hypertrophy, restores t-tubule architecture, and prevents mislocalization of connexin-43 in RV cardiomyocytes of pulmonary artery banded rats. These cellular phenotypes are paired with significant improvements in RV function. Thus, we propose 17{beta}-estradiol exerts cardioprotective effects via direct modulation of microtubules in addition to its well ascribed signaling functions.

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

Junctophilin-2 Regulates Mitochondrial Metabolism

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as Jph2 knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.

physiology↗

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↗