Mendelson Jenna B, Sternbach Jacob D, Moon Ryan A, Hartweck Lynn M, Clark Sophia R, Tollison Walt, Lahti Matthew T, Carney John P, Markowski Todd, Higgins LeeAnn, Kazmirczak Felipe, Prins Kurt W
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN.
Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN.
bioRxiv. 2025 Jan 22:2025.01.20.633954. doi: 10.1101/2025.01.20.633954.
Right 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, SC144's efficacy and molecular effects in a translational large animal model of RVD are unknown.
4-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, =5] or vehicle [PAB-Veh, =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.
SC144 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.
GP130 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.
右心室功能障碍（RVD）是多种心血管疾病死亡的危险因素，但缺乏增强右心室功能的疗法。小分子SC144通过抗炎和代谢机制抑制糖蛋白-130（GP130）信号传导，可改善啮齿动物RVD模型中的右心室功能。然而，SC144在RVD的转化性大型动物模型中的疗效和分子效应尚不清楚。
对4周龄去势雄性猪进行肺动脉环扎术（PAB）。3周后，将PAB猪随机分为2组（每天注射SC144 [2.2 mg/kg，PAB-SC144组，n = 5]或赋形剂[PAB-Veh组，n = 5]，持续3周）。5只年龄匹配的猪作为对照。心脏磁共振成像（MRI）定量评估右心室大小/功能。右心导管检查评估血流动力学。单核RNA测序描绘实验组之间细胞类型特异性变化。电子显微镜评估右心室线粒体形态。磷酸化蛋白质组学鉴定右心室中失调的激酶。脂质组学和代谢组学定量右心室组织中的脂质种类和代谢物。定量蛋白质组学检查右心室线粒体蛋白质调控。
尽管右心室后负荷相似，但SC144显著改善了右心室射血分数（对照组：60±4%，PAB-Veh组：22±10%，PAB-SC144组：37±6%）。单核RNA测序表明，与对照组相比，PAB-Veh组猪的心肌细胞丰度较低，巨噬细胞/淋巴细胞/周细胞/内皮细胞丰度较高，而SC144使其中许多变化减弱。SC144对抗了PAB诱导的心肌细胞代谢基因下调。激酶组富集分析表明，SC144抵消了右心室mTORC1的激活。相应地，SC144使右心室自噬途径蛋白重新平衡，并改善了线粒体形态。综合脂质组学、代谢组学和蛋白质组学分析表明，SC144恢复了脂肪酸代谢。最后，CellChat分析表明，SC144恢复了周细胞与内皮细胞之间的相互作用。
GP130拮抗作用可降低免疫细胞丰度升高，减少巨噬细胞和淋巴细胞中促炎基因转录，重新平衡自噬并维持心肌细胞中的脂肪酸代谢，恢复内皮细胞与周细胞之间的通讯，从而改善右心室功能。
