Stimulation of adrenergic receptors regulates proteasome function in cardiomyocytes

Abstract

Ubiquitin‐proteasome system (UPS)‐mediated proteolysis plays a central role in protein quality control and degradation in the cell. UPS dysfunction was observed in various forms of heart disease and might play an important role in the development of congestive heart failure (CHF). However, very little is known about how UPS proteolytic function is regulated in the heart.The sympathetic nervous system (SNS) activity is increased during CHF. As an initial step to investigate if and how the SNS regulates UPS function in the heart, we employed neonatal rat ventricular myocytes (NRVM) culture. To monitor UPS function, a validated UPS surrogate substrate (a modified Green Fluorescent Protein, GFPu) and a red fluorescent protein (RFP, not a specific substrate of the UPS) were co‐expressed in cultured NRVMs through adenoviral gene deliveryWe found that both stimulation of the beta 1 receptor with dobutamine and stimulation of the alpha 1 receptor with phenylephrine significantly reduced the GFPu/RFP ratio, suggesting an enhancement of UPS function. We have also discovered that the phosphorylation status of the Rpt6 subunit of the 19S proteasome and the beta 5 subunit of the 20S proteasome was markedly altered by stimulating each of the receptors. These preliminary findings suggest that SNS may play an important role in regulating cardiac proteasomes. Funding: NIH HL085629, HL072166, and HL068936.