Heart failure & cardiomyopathies
Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure
Authors' conclusion
Our results suggest that PDE3A regulates SERCA2 activity through direct binding, independently of the catalytic activity of PDE3A. Targeting the SERCA2/PDE3A interaction prevented cardiac mortality after AB, most likely by improving cardiac contractility.
Study context
- Population
- Mice undergoing aortic banding (AB) or sham surgery
- Participants
- 148 mice
- Comparison
- rAAV9-OptF vs rAAV9-Ctrl vs PBS, before aortic banding or sham surgery
- Outcome
- Cardiac mortality and cardiac function
- Follow-up
- 20 weeks
Methodological details2 consecutive randomized, blinded, and controlled preclinical trials, animal study (mice)
- 2 consecutive randomized, blinded, and controlled preclinical trials
- Animal study (mice)
Main finding
As reported in the abstract
Cardiac mortality · 20 weeks after AB
Hazard ratio (95% CI)
rAAV9-OptFvs rAAV9-Ctrl
0.26(0.11–0.63)
rAAV9-OptFvs PBS
0.28(0.09–0.90)
Further findings
Contractility and cardiac remodeling after aortic banding
- Improved contractility with rAAV9-OptF vs rAAV9-Ctrl
- No difference in cardiac remodeling vs rAAV9-Ctrl
SERCA2/PDE3A colocalization and interaction sites
- PDE3A colocalized with SERCA2 in human nonfailing, human failing, and rodent myocardium
- Amino acids 277-402 of PDE3A bound directly to amino acids 169-216 within the actuator domain of SERCA2
SERCA2 activity with disruption of PDE3A from SERCA2
- Increased SERCA2 activity in normal and failing cardiomyocytes
- Increased SERCA2 activity also with protein kinase A inhibitors and in phospholamban-deficient mice
- No effect in mice with cardiomyocyte-specific inactivation of SERCA2
- Cotransfection of PDE3A reduced SERCA2 activity in HEK293 vesicles
Original publication
Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure. Circulation. Published 6 March 2023. doi:10.
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