Kaempferol alleviates right ventricular hypertrophy in high-altitude pulmonary hypertension rats by modulating the AMPK/ACC/CPT1B axis and the AMPK-mediated LDHA/PDHA1 pathway
Abstract
This study evaluates the protective effects of kaempferol on right ventricular (RV) structure and function in a rat model of high-altitude pulmonary hypertension (HAPH) and explores the underlying mechanisms. Male Sprague-Dawley rats (n = 57) were exposed to a simulated high-altitude environment (5000 m) for 28 days to induce HAPH, followed by the administration of kaempferol (25, 50, 100 mg kg-1 day-1) or sildenafil (30 mg kg-1 day-1). Echocardiography, hemodynamic measurements, and histopathological analyses revealed that kaempferol significantly reduced the RV/(LV + S) index, mean pulmonary artery pressure (mPAP), mean right ventricular systolic pressure (mRVSP), and RV free wall thickness (RVFWT); increased the pulmonary artery acceleration time (PAAT), PAAT/pulmonary artery ejection time (PAET) ratio, tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary artery coupling indices (TAPSE/mPAP and TAPSE/pulmonary artery systolic pressure [PASP]); and attenuated RV remodeling (assessed by H&E staining, Masson's trichrome staining, and transmission electron microscopy). Phosphoproteomic screening identified AMPK signaling as a key pathway modulated by kaempferol. In vivo, kaempferol downregulated the hypertrophy marker (MYH7B), suppressed the AMPK/ACC/CPT1B axis (at 25/50 mg kg-1), and reduced the LDHA (at 50/100 mg kg-1) and p-PDHA1 levels (at 25/50 mg kg-1) in RV tissues. Using the CCK-8 assay, fluorescence microscopy, and hypertrophy marker (BNP/MYH7B)…
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