The ApoA5-RND3 axis attenuates right heart failure in pulmonary arterial hypertension by targeting ATP2A2-dependent endoplasmic reticulum calcium homeostasis remodeling to ameliorate mitochondrial dysfunction

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by progressive pulmonary vascular remodeling and right heart failure. Apolipoprotein A5 (ApoA5) is vital for lipid metabolism and cardiovascular function, but its role in PAH-related right heart failure has remained largely unexplored. This study aimed to explore a previously unrecognized mechanism by which ApoA5 regulates endoplasmic reticulum (ER) calcium homeostasis and mitochondrial dysfunction in right heart failure. Using Sugen-Hypoxia-induced PAH mouse models (AAV9-mediated ApoA5 overexpression or rhApoA5 treatment) and Ang II-induced cardiac fibroblasts, we evaluated relevant functional changes and explored the underlying mechanisms using RNA sequencing and molecular assays. ApoA5 overexpression significantly improved right ventricular function, reduced right ventricular systolic pressure (from 56.6 to 35.4 mmHg, P < 0.001), and attenuated right ventricular hypertrophy index (from 0.562 to 0.382, P < 0.001) and fibrosis ( P < 0.001) in SuHx mice. These benefits were accompanied by a reduction in endoplasmic reticulum (ER) stress indicators, alongside mitigation of oxidative stress injury ( P < 0.001). In cardiac fibroblasts, ApoA5 suppressed proliferation, migration, and fibrotic marker expression, while reducing ROS and restoring mitochondrial membrane potential and ATP production ( P < 0.05). Mechanistically, ApoA5 upregulated RND3, which bound to and stabilized ATP2A2 mRNA, thereby restoring ER calcium homeostasis and alleviating mitochondrial dysfunction. Notably, RND3 knockdown partially reversed ApoA5-mediated protective effects, confirming the axis dependency ( P < 0.05). ApoA5-RND3 axis attenuated PAH-related right heart failure by targeting ATP2A2-dependent ER calcium homeostasis remodeling to ameliorate mitochondrial dysfunction. Our findings identify ApoA5, RND3, and ATP2A2 as promising therapeutic targets for PAH, with potential clinical applications in early diagnosis and combination therapy. Moreover, targeting the ER–mitochondria axis represents a valuable translational approach for future PAH interventions.