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GP130 Antagonism Enhances Porcine RV Function
Jenna B Mendelson1, Jacob D Sternbach2, Minwoo Kim2
1Department of Integrative Biology and Physiology (J.B.M.), University of Minnesota, Minneapolis, MN.
Background:
Right ventricular (RV) dysfunction is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of GP130 (glycoprotein-130) signaling with the small molecule SC144 improves RV function in rodent RV dysfunction via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy and molecular effects in a translational large animal model of RV dysfunction are unknown.
Methods:
Four-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 magnetic resonance imaging 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 and serum. Quantitative proteomics examined RV mitochondrial protein regulation. Confocal microscopy evaluated alterations in cardiomyocyte size, macrophage abundances, capillary density, and pericyte/endothelial cell localization patterns.
Results:
SC144 significantly improved RV ejection fraction (control: 60±4%; PAB-Veh: 22±10%; PAB-SC144: 37±6%) without altering RV afterload. Single-nucleus RNA sequencing demonstrated that PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared with control, and many of these changes were blunted by SC144. Immunohistochemistry validated the reduction in RV macrophage infiltration by SC144. Both transcriptomics and proteomics approaches demonstrated that SC144 combatted the downregulation of cardiomyocyte metabolic genes/proteins induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 (mammalian target of rapamycin complex 1) activation. Correspondingly, SC144 rebalanced the RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed that SC144 restored fatty acid metabolism. Finally, CellChat analysis, cardiomyocyte RNAseq analysis, and histological examination suggested SC144 rebalanced pericyte-endothelial cell interactions and blunted cardiomyocyte HIF1 (hypoxia-induced factor 1) activation.
Conclusions:
GP130 antagonism blunts RV immune cell infiltration, reduces proinflammatory gene programs in macrophages and lymphocytes, rebalances autophagy, and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte homeostasis to mitigate cardiomyocyte hypoxia and ultimately augments RV function.
Insights
The small molecule SC144 improves right ventricular (RV) function in a large animal model by reducing inflammation and metabolic dysfunction. This study shows SC144 enhances RV ejection fraction and preserves cardiomyocyte health.
Area of Science:
- Cardiovascular Research
- Translational Medicine
- Pharmacology
Background:
- Right ventricular (RV) dysfunction is a significant risk factor for mortality in cardiovascular diseases, yet effective therapies remain limited.
- The small molecule SC144 has shown promise in improving RV function in rodent models through anti-inflammatory and metabolic pathways.
- The efficacy and underlying molecular mechanisms of SC144 in a large animal model of RV dysfunction require investigation.
Purpose of the Study:
- To evaluate the therapeutic potential of SC144 in a translational large animal model of RV dysfunction.
- To elucidate the molecular and cellular mechanisms by which SC144 improves RV function.
- To assess the impact of SC144 on RV hemodynamics, cellular composition, metabolism, and mitochondrial function.
Main Methods:
- Pulmonary artery banding (PAB) was performed in pigs to induce RV dysfunction.
- PAB pigs were randomized to receive daily SC144 injections or vehicle control for 3 weeks.
- Comprehensive analyses included cardiac MRI, right heart catheterization, single-nucleus RNA sequencing, electron microscopy, phosphoproteomics, lipidomics, metabolomics, and quantitative proteomics.
Main Results:
- SC144 significantly improved RV ejection fraction without altering RV afterload.
- SC144 treatment blunted PAB-induced increases in RV macrophage, lymphocyte, and pericyte/endothelial cell abundances and reduced macrophage infiltration.
- SC144 counteracted PAB-induced downregulation of cardiomyocyte metabolic genes, normalized mTORC1 signaling, improved mitochondrial morphology, restored fatty acid metabolism, and rebalanced pericyte-endothelial cell interactions.
Conclusions:
- GP130 antagonism with SC144 mitigates RV dysfunction by reducing inflammation, preserving cardiomyocyte metabolism, and restoring cellular homeostasis.
- SC144 demonstrates significant therapeutic potential for RV dysfunction in a large animal model, offering a promising avenue for clinical translation.
- The study highlights SC144's multifaceted effects on RV pathophysiology, including anti-inflammatory, metabolic, and vascular protective mechanisms.
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