PPARα Activation Attenuates Right Ventricular Hypertrophy by Regulating Myocardial Glucose and Lipid Metabolism in High-Altitude Pulmonary Hypertension In Vivo and In Vitro.

UNLABELLED: Zhang, Xiaoying, Jiajia Wu, Yuchan Zhang, Yuquan Xie, Qi Si, Shadi Li, and Yiwei Han. PPARα activation attenuates right ventricular hypertrophy by regulating myocardial glucose and lipid metabolism in high-altitude pulmonary hypertension in vivo and in vitro. High Alt Med Biol. 00:00-00, 2026. BACKGROUND: Right ventricular hypertrophy (RVH) and cardiac function are key prognostic determinants in patients with high-altitude pulmonary hypertension. Meanwhile, their initiation and progression are driven by disturbances in glucose and lipid metabolism in cardiomyocytes. OBJECTIVE: This study established an SU5416-associated hypobaric hypoxia-induced RVH (H-RVH) rat model and a CoCl2-induced hypoxic cardiomyocyte model to explore glucose and lipid metabolism alterations and mechanisms. METHODS: The metabolomic cluster analysis of metabolites primarily focused on lipid metabolism, along with Kyoto Encyclopedia of Genes and Genomes-enriched pathways, including glycolysis/gluconeogenesis, glycerophospholipid metabolism, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. RESULTS: Compared with the control group, glucose transporter-4 (GLUT-4) and pyruvate dehydrogenase (PDH) kinase were increased by 320% and 220% in H-RVH rats, respectively (p < 0.05), whereas PDH and citrate synthase (CS) were decreased by 39% and 58%, respectively (p < 0.05), collectively indicating a shift toward glycolysis and away from glucose oxidation. Seahorse Extracellular Flux (XF) assay revealed that basal glycolysis and compensatory glycolytic capacity were significantly elevated in the CoCl2-induced hypoxic cardiomyocyte model compared with the control group (288.5 ± 9.82 vs. 344.1 ± 10.24, 335.9 ± 11.58 vs. 385.7 ± 14.74, p < 0.05). The expression levels of PPARα and carnitine palmitoyltransferase 1α (CPT-1α) in the H-RVH group were 48% and 56% lower than those in the control group, respectively (p < 0.05); acetyl-CoA and adenosine triphosphate (ATP) were also reduced (p < 0.05). Fenofibrate mitigated CoCl2-induced hypoxic damage through 1.6-fold activation of PPARα. Cardiac-specific PPARα overexpression via an adeno-associated virus (AAV9) effectively attenuated RVH, as evidenced by the reduction in Fulton's index (0.37 ± 0.09 vs. 0.46 ± 0.02, p < 0.05), right ventricular anterior wall diastolic (RVAWd) (0.64 ± 0.04 vs. 0.93 ± 0.02, p < 0.01) and RVAWs (0.68 ± 0.05 vs. 0.97 ± 0.02, p < 0.01). In contrast, PPARα knockdown did not significantly alter the Fulton index but markedly increased both RVAWd (1.00 ± 0.01 vs. 0.77 ± 0.03, p < 0.01) and RVAWs (1.00 ± 0.02 vs. 0.70 ± 0.05, p < 0.01). CONCLUSION: In this study, our findings demonstrate that PPARα exerts a protective effect against RVH, at least in part, by promoting fatty acid oxidation through upregulation of its downstream target proteins CPT-1 and acyl-CoA oxidase 1.