Endothelial TFEB Activation Inhibits Hypoxia-Induced Pulmonary Hypertension 

Pulmonary hypertension (PH) is a vascular disorder affecting people of all ages, with a higher prevalence in the elderly. Approximately 25 million patients worldwide who suffer from PH have chronic obstructive pulmonary disease, sleep apnea, or interstitial lung disease. In the United States, treatment for each patient is estimated at $80,000, a cost that is unfeasible for many patients in developing countries and presents a significant financial burden for both individuals and society. Endothelial dysfunction, elevated contractility and progressive adverse remodeling of pulmonary arteries are major characteristics in PH progression. Most clinically used drugs to treat PH are vasodilators that provide varying degrees of therapeutic benefits mainly for patients with mild or moderate PH, but they are less effective for patients with advanced vascular narrowing and severe PH. Therefore, it is crucial to understand the detailed mechanisms that mediate endothelial dysfunction and pulmonary vascular narrowing to identify new targets for developing more effective strategies against PH.Recent emerging evidence suggests that transcription factor EB (TFEB) plays a crucial role in maintaining cardiovascular function. Our preliminary findings demonstrate a decreased TFEB expression in endothelial cells of pulmonary arteries from patients with idiopathic pulmonary hypertension or mice with hypoxia-induced pulmonary hypertension, as well as in hypoxia-exposed human pulmonary artery endothelial cells. Therefore, TFEB may serve as a potential therapeutic target for the management of pulmonary hypertension. Based on these promising observations, we hypothesise that activation of endothelial TFEB assists in maintaining the healthy function and structure of pulmonary blood vessels. However, the deficiency of TFEB plays a significant role in causing endothelial dysfunction during the development and progression of PH in pulmonary blood vessels. To test this crucial hypothesis, we aim to investigate three inter-related objectives: (1) the role of endothelial TFEB in the pathogenesis of hypoxia-induced pulmonary hypertension, (2) the mechanisms for TFEB’s regulation of the expression of endothelin-1 and eNOS, and (3) the impact of TFEB lactylation on its expression and function, as well as its effect in the pathogenesis of hypoxiainduced PH.This study aims to bridge the knowledge gap regarding the regulatory mechanisms of TFEB expression and activity in pulmonary vascular endothelial cells. It investigates how these mechanisms contribute to the function and structure of pulmonary arteries. Additionally, we aim to establish TFEB as a potential target for drug screening to identify new candidates for preventing and treating PH.