ApoA5–RND3 pathway protects the right heart in pulmonary arterial hypertension

Pulmonary arterial hypertension is a lethal disease driven by progressive remodeling of the pulmonary vasculature, and its most feared endpoint is right heart failure, in which the right ventricle strains against elevated pulmonary pressures until it can no longer maintain output. A study published in the Journal of Translational Medicine now reports a previously unrecognized molecular route by which the heart’s right side may be shielded from this decline. The work centers on apolipoprotein A5, a protein best known for its role in lipid metabolism and cardiovascular function, whose involvement in right heart failure associated with pulmonary arterial hypertension had remained largely unexplored until now.

The research team used Sugen-hypoxia mouse models, a standard experimental approach for reproducing the vascular and cardiac pathology of pulmonary arterial hypertension. In these animals, apolipoprotein A5 was delivered either through AAV9-mediated overexpression or through recombinant human ApoA5 treatment. The investigators also studied angiotensin II-induced cardiac fibroblasts in culture and applied RNA sequencing alongside molecular assays to trace the pathway linking the protein to cellular function. The combined design allowed the team to evaluate functional changes in living animals while dissecting the underlying mechanisms at the cellular and transcriptomic level.

The results were striking. Apolipoprotein A5 overexpression significantly improved right ventricular function in the Sugen-hypoxia mice and reduced right ventricular systolic pressure from 56.6 to 35.4 millimeters of mercury, a difference the authors report as highly significant. The treatment also attenuated the right ventricular hypertrophy index, which fell from 0.562 to 0.382, and reduced fibrosis in the right ventricle. These structural and hemodynamic benefits were accompanied by a reduction in endoplasmic reticulum stress indicators and by diminished oxidative stress injury, suggesting that the protein acts on several converging pathways of cellular damage rather than a single target.

In the cultured cardiac fibroblasts, apolipoprotein A5 suppressed proliferation, migration, and the expression of fibrotic markers, processes that contribute to the stiffening and remodeling of heart tissue. The protein also reduced reactive oxygen species while restoring mitochondrial membrane potential and ATP production, both of which are hallmarks of healthy energy metabolism. Because mitochondria and the endoplasmic reticulum communicate closely through calcium signaling, these findings pointed the investigators toward the interface between the two organelles as the likely site of the protein’s protective action.

The mechanistic core of the study emerged from the transcriptomic and molecular analyses. Apolipoprotein A5 was found to upregulate RND3, a small GTP-binding protein, which in turn bound to and stabilized the messenger RNA of ATP2A2, the gene encoding the sarcoendoplasmic reticulum calcium pump. By preserving this calcium pump, the pathway restored endoplasmic reticulum calcium homeostasis and thereby eased the mitochondrial dysfunction that follows calcium dysregulation. When the researchers knocked down RND3, the benefits conferred by apolipoprotein A5 were partially reversed, confirming that RND3 is a required mediator of the protective effect and that the ApoA5–RND3 axis operates through ATP2A2-dependent calcium handling.

The authors conclude that the ApoA5–RND3 axis attenuates right heart failure in pulmonary arterial hypertension by targeting ATP2A2-dependent endoplasmic reticulum calcium homeostasis remodeling and ameliorating mitochondrial dysfunction. On the strength of these findings, they identify apolipoprotein A5, RND3, and ATP2A2 as promising therapeutic targets for a disease in which treatment options for the failing right ventricle remain limited. Beyond the specific pathway, the study frames the endoplasmic reticulum–mitochondria axis as a valuable translational direction for future interventions in pulmonary arterial hypertension, offering a molecular rationale for therapies aimed at restoring calcium balance and energy metabolism in the stressed right heart.

Subject of Research: Molecular mechanism of ApoA5–RND3 axis in pulmonary arterial hypertension right heart failure

Article Title: 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

Article References: Chen, J., Chen, Y., Chen, W., Tan, Y., Wang, T., Xie, Y., & Luo, J. (2026). 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. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09121-x

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09121-x

Keywords: ApoA5-RND3, axis, attenuates, right, heart, failure, pulmonary, arterial, hypertension, targeting, ATP2A2-dependent, endoplasmic