Kaempferol Protects Pulmonary Vascular Endothelial Function in Rats with High Altitude Pulmonary Hypertension by Regulating RAS System and AMPK/Arg2/eNOS Signaling Pathway

Abstract

BackgroundPrevious studies have found that kaempferol can relieve pulmonary hypertension (PH).ObjectiveExplore the protective impact of kaempferol on pulmonary vascular endothelium in rats with high altitude pulmonary hypertension (HAPH).Materials and methodsIn a simulated altitude of 5000 m environment, rats were induced to develop HAPH after continuous intragastric administration of kaempferol (25, 50 and 100 mg·kg−1) and Sildenafil (30 mg·kg−1) for 28 days. Assessment of isolated pulmonary arterial rings in rats and relevant indicators in lung tissue was performed, with the mechanism of action investigated using Western blotting.ResultsKaempferol effectively dilates rat pulmonary arterial rings, with an EC50 of 55.75 μmol/L. L-NAME can effectively counteract the vasodilatory effect of kaempferol. Acetylcholine demonstrated better relaxation of pulmonary arterial rings in HAPH rats after kaempferol intervention. Elastic Van Gieson staining (EVG) and immunohistochemistry (CD31) results indicate that kaempferol can partially protect pulmonary vascular endothelial function in HAPH rats. Western blotting reveals that kaempferol has the ability to regulate the Renin-Angiotensin System (RAS). This leads to a compensatory increase in eNOS expression, upregulation of AMPK activity, and downregulation of eNOS monomer/dimer levels.ConclusionsKaempferol can improve pulmonary vascular endothelial dysfunction caused by chronic hypoxia by upregulating the phosphorylation level of AMPK, regulating the RAS system, and inhibiting eNOS uncoupling, thereby achieving vasodilation and endothelial protection.