OBJECTIVE

Proteasome activation by the cAMP-dependent protein kinase (PKA) was long suggested and recent studies using both cell cultures and genetically engineered mice have established that direct phosphorylation of RPN6/PSMD11 at Serine14 (pS14-RPN6) mediates the activation of 26S proteasomes by PKA. Genetic mimicry of pS14-RPN6 has been shown to be benign at baseline and capable of protecting against cardiac proteinopathy in mice. Here we report the results from a comprehensive baseline characterization of the Rpn6 mice (S14A), the first animal model of genetic blockade of the activation of 26S proteasomes by PKA.

METHOD

Wild type and homozygous S14A littermate mice were subjected to serial M-mode echocardiography at 1 through 7 months of age, to left ventricular (LV) catheterization via the carotid artery for assessment of LV mechanical performance, and to cardiac gravimetric analyses at 26 weeks of age. Mouse mortality and morbidity were monitored daily for up to one year. Males and females were studied in parallel.

RESULTS

Mice homozygous for S14A were viable and fertile and did not show discernible developmental abnormalities or increased mortality or morbidity compared with their Rpn6 wild type littermates by at least one year of age, the longest cohort observed thus far. Neither serial echocardiography nor hemodynamic assessments detected a remarkable difference in cardiac morphometry and function between S14A and wild type littermate mice. No cardiac gravimetric difference was observed.

CONCLUSION

The findings of the present study indicate that genetic blockade of the activation of 26S proteasomes by PKA is well tolerated by mice at baseline. Therefore, the S14A mouse provides a desirable genetic tool for further investigating the in vivo pathophysiological and pharmacological significance of pS14-RPN6.