Methyleugenol alleviates pulmonary vascular remodeling in rats with high-altitude pulmonary hypertension by improving pulmonary smooth muscle cell function

Abstract

Pulmonary hypertension is divided into five groups, and chronic exposure to hypoxia causes pulmonary hypertension in the third group -- high altitude pulmonary hypertension, which is commonly seen in patients with chronic obstructive pulmonary disease, sleep-disordered breathing, and interstitial lung disease. Its clinicopathological features include right heart overload and right ventricular hypertrophy, with severe patients potentially experiencing right heart failure or even death. The pathogenesis of high altitude pulmonary hypertension is complex; it includes oxidative stress, mitochondrial dysfunction, apoptosis, and pyroptosis. Pharmacological therapy may alleviate the condition if immediate descent to lower altitudes or supplemental oxygen is not possible. Herein, we preliminarily investigated the effect of methyleugenol on high altitude pulmonary hypertension through in vitro and in vivo experiments. Methyleugenol alleviated pulmonary arteriole constriction by acting on potassium ion channels, and inhibited the proliferation of pulmonary artery smooth muscle cells(PASMCs) by decreasing and reactive oxygen species levels, as well as inhibiting the expression of HIF-1α. The cardiac systolic function improved and mitochondrial structure of pulmonary artery smooth muscle cells in rats with high altitude pulmonary hypertension was significantly improved after methyleugenol gavage intervention, and malondialdehyde levels in serum of rats were decreased while those of superoxide dismutase and glutathione increased, suggesting that the reduction of oxidative stress may be one of the mechanisms to improve mitochondrial function. Western blot experiments showed that methyleugenol regulated the oxidative stress level in rats by activating Nrf2/HO-1 signaling pathway, activate p27Kip1, inhibit CDK4/CCND1/ p-ERK1/2 and inhibited HIF-1α/RASSF1/Ras axis to inhibit cell proliferation, thereby improving the occurrence and development of high altitude pulmonary hypertension in rats. The results of this study reveal that methyl eugenol has the potential to alleviate pulmonary vasoconstriction and remodeling in rat models of high-altitude pulmonary hypertension, providing a scientific basis for the application of this compound in improving pulmonary vascular remodeling.