Compensatory Activation of PI3K/AKT Signaling Protects Against Cardiomyocyte Apoptosis in Pulmonary Hypertension–Induced Right Ventricular Dysfunction

Background Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder marked by increased pulmonary vascular resistance and poor prognosis. Right ventricular (RV) dysfunction, rather than pulmonary vascular pathology, is the principal determinant of mortality. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway regulates cardiomyocyte survival and apoptosis; however, its role in PH-induced RV remodeling remains poorly defined. Methods A hypobaric hypoxia–induced PH model was generated in C57BL/6J mice. Echocardiography, histology, RNA sequencing, quantitative PCR, Western blotting, and immunofluorescence were employed to assess RV structure, apoptosis, fibrosis, and PI3K/AKT activation. In parallel, H9C2 cardiomyocytes were treated with angiotensin II, with or without the PI3K inhibitor LY294002, to evaluate apoptotic responses. Results PH mice developed RV dysfunction characterized by increased apoptosis and fibrosis. Transcriptomic analysis revealed marked activation of the PI3K/AKT pathway. Bax expression was significantly upregulated, whereas Bcl-2 was downregulated at both mRNA and protein levels. Pharmacological inhibition of PI3K/AKT signaling aggravated angiotensin II–induced apoptosis in H9C2 cells. In addition, Ki67 staining indicated limited cardiomyocyte cell cycle re-entry, reflecting a compensatory yet insufficient proliferative response. Conclusions PI3K/AKT signaling is compensatorily activated during PH-induced RV remodeling and provides partial protection against apoptosis. However, this response fails to offset apoptotic cell loss, contributing to RV dysfunction. Precise modulation of PI3K/AKT signaling may represent a potential therapeutic approach for PH-associated right heart failure.