Too much of a good thing is bad: proteasome inhibition induces stressed hearts to fail

Abstract

This editorial refers to ‘Proteasome functional insufficiency activates the calcineurin–NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts’ by M. Tang et al ., pp. 424–433, this issue. A fine balance between protein synthesis and protein degradation regulates cellular homeostasis. Cardiac remodelling is a common response of the heart to changes in physiological or pathological demand. Hypertrophic growth is the primary mechanism through which the heart normalizes ventricular wall stress. It is characterized by an increase in the volume of individual cardiac myocytes, which can be the result of an acceleration of synthesis or a reduced degradation rate of proteins. However, while the synthesis rate has always been shown to be increased, protein degradation has been shown to be either accelerated or unchanged in hypertrophic hearts and inhibited by induction of cardiac work or high aortic pressure in Langendorff preparations.1 The ubiquitin–proteasome system (UPS) is one of the two major proteolytic systems that degrade most cellular, nuclear, and myofibrillar proteins in cells, as recently reviewed in a Spotlight issue of Cardiovascular Research .2 A main function of the UPS is to prevent accumulation of damaged, misfolded, and mutant proteins. Over the past two decades, the UPS has been increasingly recognized as a main player in regulating a multitude of cellular processes and dynamics. Two consecutive steps characterize the UPS. The first one is ubiquitination, which consists of the addition of several ubiquitin moieties onto a target intended for degradation and which involves the concerted action of at least three … *Corresponding author. Tel: +49 40 7410 57208; fax: +49 40 7410 55925, Email: l.carrier{at}uke.uni-hamburg.de