GP130 Antagonism Enhances Porcine RV Function.

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.