TRIB2 promotes pulmonary artery smooth muscle cell proliferation through SERCA2 ubiquitination in pulmonary hypertension

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling (PVR) driven by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). This study investigated the role of tribbles homolog 2 (TRIB2), a pseudokinase protein, in PH-associated PASMC proliferation. Using platelet-derived growth factor-BB (PDGF-BB)-stimulated primary human PASMCs, hypoxia/Su5416-induced PH mice, and monocrotaline-treated PH rats, we demonstrated elevated TRIB2 levels in both rodent PH models and PDGF-BB-stimulated PASMCs. TRIB2 knockdown via siRNA significantly inhibited cell cycle progression and suppressed PASMC proliferation, migration, and anti-apoptotic activity. Mechanistically, TRIB2 mediated ubiquitin-mediated degradation of sarco/endoplasmic reticulum CA²⁺-ATPase 2 (SERCA2) through the E3 ubiquitin Ligase SMAD specific E3 ubiquitin protein Ligase 1 (SMURF1). This process induced endoplasmic reticulum stress and activated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1s (XBP1s) pathway, accelerating cell cycle, promoting PASMC hyperproliferation, and inhibiting Apoptosis. Furthermore, in vivo, Trib2 knockdown significantly ameliorated PVR and pulmonary hemodynamics in PH rats. Our findings demonstrate that TRIB2 contributes to PASMC hyperproliferation through SERCA2 ubiquitination in PH, highlighting TRIB2 as a potential therapeutic target for PH treatment.

Cell cycle; Cell proliferation; Endoplasmic reticulum stress; Pulmonary hypertension; Pulmonary vascular remodeling; SMAD specific E3 ubiquitin protein ligase 1; Sarco/endoplasmic reticulum Ca(2+)-ATPase 2; Tribbles homolog 2; Ubiquitination.