Ubiquitination is involved in the alteration of peripheral acetylcholine mediation in the aging heart

Abstract

It is known that aging and heart disease both result in an increase in sympathetic nervous system activity and a decrease in parasympathetic nervous system (PSNS) activity, which may contribute to age‐related cardiac dysfunction and remodeling. However, the mechanisms underlying impairment of the PSNS in aging remain to be fully understood. Utilizing young (1–2 month) and old (11–12 month) mice, it was determined that a peripheral and pre‐synaptic mechanism is involved in the diminishment of baroreflex sensitivity (BRS) and loss of response to rostral‐severed vagal stimulation within the hearts of aging mice. Analysis of protein expression of aging mouse atria with fat pad reveals alteration of the proteins involved in acetylcholine (Ach) mediation. A significant decrease in Ach synthesizing protein, choline acetyltransferase (ChAT), as well as a significant decrease in the upper band of the Ach packaging protein, vesicular Ach transporter (VAchT) was found. In contrast, a significant upregulation of the upper band of the rate‐limiting protein, choline transporter (CHT), is seen in the aging animals indicative of a compensatory mechanism. Further investigation utilizing immunoprecipitation has revealed that the upper band of VAchT, but not CHT is ubiquitinated. Given the role of ubiquitination in protein trafficking and turnover, the altered ubiquitination of VAChT seen in this study may impact VAChT distribution and activity, and thus PSNS transmission at intra‐atrial ganglia in aging. This work was supported by AHA grant No.0835256N, NIH INBRE grant No.P20 RR016479, NIH grant No. 1R03AG033291, and the BBS bridge grant.