Cardiomyocyte PRL2 Promotes Cardiac Hypertrophy via Directly Dephosphorylating AMPKα2.

Summary

This mechanistic study identifies PRL2 as a phosphatase that directly binds to and dephosphorylates AMPKα2, thereby promoting pathological hypertrophy, fibrosis, and dysfunction. PRL2 expression is elevated in hypertrophic myocardium (mouse and human HF), while genetic loss of PRL2 preserves AMPK signaling and attenuates remodeling in Ang II and TAC models.

Key Findings

• PRL2 expression is significantly upregulated in hypertrophic myocardium from mice and in human heart failure tissue.
• Genetic PRL2 deficiency attenuates hypertrophy, fibrosis, and dysfunction in Ang II infusion and transverse aortic constriction models.
• PRL2 directly interacts with and dephosphorylates AMPKα2, dampening AMPK signaling; maintaining AMPK activity mitigates remodeling.

Clinical Implications

Although preclinical, targeting PRL2 could preserve AMPK activity to prevent or reverse pathological hypertrophy and heart failure; medicinal chemistry efforts to develop selective PRL2 inhibitors or degraders are warranted.

Limitations

• Preclinical study without pharmacologic PRL2 inhibition in vivo.
• Translational relevance requires validation in large-animal models and safety assessment.

Future Directions

Develop selective PRL2 inhibitors/degraders; test efficacy across hypertrophy etiologies; assess safety and target engagement in large animals; integrate cardiac metabolism endpoints.