Kaempferol Alleviates Right Ventricular Hypertrophy in High Altitude Pulmonary Hypertension Rats by Modulating AMPK/ACC/CPT1B Axis and AMPK-mediated LDHA/PDHA1 Pathway

Abstract

To evaluate the effect of Kaempferol on right ventricle (RV) structure/function in high-altitude pulmonary hypertension (HAPH) rats and to explore the underlying mechanisms. Methods: Male Sprague-Dawley rats (n=57) were exposed to a simulated high-altitude environment of 5000 meters for 28 days. Following administration of kaempferol (25, 50, 100 mg/kg/day) and sildenafil (30 mg/kg/day), RV structure (RVFWT, RV free wall thickness)，function (TAPSE，tricuspid annular plane systolic excursion; PAAT, pulmonary artery acceleration time; PAET, pulmonary artery ejection time) and RV-PA coupling (TAPSE/mPAP, TAPSE/PASP, and TAPSE/PAAT ratios) were evaluated using echocardiography, hemodynamic measurements (right heart catheterization), and histopathological analysis (HE, Masson’s trichrome staining and TEM). Phosphoproteomics was used to screen the candidate targets and western blotting verify were employed. Cell viability (CCK-8 assay), cell area (fluorescence microscopy), and hypertrophy markers (BNP/MYH7B) were evaluated for the optimal Ang II concentration and effective kaempferol range. AICAR (AMPK activator) was used to confirm the target. Results: Kaempferol lowered RV/ (LV + S) index, mPAP, mRVSP; increased PAAT, PAAT/PAET, TAPSE, TAPSE/mPAP, TAPSE/PASP; and attenuated RV remodeling in HAPH rats. And AMPK was screened as one of key pathways in RV hypertrophy. Kaempferol down-regulated MYH7B, suppressed AMPK/ACC/CPT1B axis (25/50 mg/kg), down-regulated LDHA (50/100 mg/kg) and p-PDHA1 level (25/50 mg/kg) in RV of HAPH rat. In vitro employing optimized concentrations of Ang II (1×10⁻⁶ M) and kaempferol (40μM), the effects of kaempferol on AMPK-mediated glucose and fatty acid oxidation were reversed by AICAR co-treatment. Conclusions: Kaempferol protected RV structure and function and attenuated RV remodeling in HAPH rats, potentially through modulation of AMPK/ACC/CPT1B axis and AMPK-mediated LDHA/PDHA1 pathway.