Osteopontin Regulates Right Ventricular Failure through Integrin αvβ3/PERK/CHOP-Dependent Inflammatory and Apoptotic Pathways

Xiaomei Yang¹Xuyang Wang^2,3Kai Li¹Qiming Deng⁴Yonghao Hou¹Guangmin Xi⁵Kangping Lu^2,6ZiHua Liu^1,2Yu Bai^1,2Jianbo Wu^7,8,9Jingui Yu¹Peng Zhang^1*

• ¹Qilu Hospital, Shandong University, Jinan, Shandong Province, China
• ²Shandong University, Jinan, Shandong Province, China
• ³Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
• ⁴Beijing Anzhen Hospital, Capital Medical University, Chaoyang District, Beijing, China
• ⁵School of Life Science, Qilu Normal University, Jinan, Shandong Province, China
• ⁶The Second Hospital of Shandong University, Jinan, Shandong Province, China
• ⁷Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
• ⁸Shandong Institute of Anesthesia and Respiratory Critical Care Medicine, the First Affiliated Hospital of Shandong First Medical University, Jinan, China
• ⁹Shandong Provincial Clinical Research Center for Anesthesiology, the First Affiliated Hospital of Shandong First Medical University, Jinan, China

Right ventricular failure is a life-threatening condition commonly associated with obvious immune responses in its progression. This study aims to investigate the role of osteopontin (OPN ) in right ventricular failure pathogenesis and evaluate its potential as a therapeutic target.This study adopted a multi-level design. First, immune-related differentially expressed genes (IRDEGs) were identified using the GEO database (GSE161473) and immune cell composition analysis via ImmuCellAI. A right ventricular failure (RVF) rat model was established, and Western blot, RT-qPCR, and immunohistochemical/immunofluorescence analyses were performed to assess OPN expression and inflammatory infiltration. In vitro, neonatal rat cardiomyocytes were treated with recombinant OPN to examine changes in endoplasmic reticulum stress markers, while the Integrin-αvβ3 inhibitor LM609 was used to delineate OPN's mechanism of action. Finally, in a clinical study, serum OPN levels were measured by ELISA and compared with NT-proBNP through correlation and Receiver Operating Characteristic (ROC) analyses.We found that OPN triggered cardiomyocyte inflammatory responses by activating endoplasmic reticulum stress via the Integrin-αvβ3/PERK/CHOP pathway. OPN exhibited concentration-dependent effects on cardiomyocyte survival: at 2 μg/ml it showed protective effects through BCL-2 modulation, while higher concentrations promoted apoptosis.Importantly, serum OPN levels strongly correlated with NT-proBNP and disease severity in RVF patients.These findings identify OPN as a crucial mediator of RVF pathogenesis through the regulation of inflammatory and apoptotic pathways, establishing its potential as a promising therapeutic target.