Proteasome inhibitors and cardiac cell growth

Abstract

Activation of the ubiquitin-proteasome system has been described in different models of cardiac hypertrophy. Cardiac cell growth in response to pressure or volume overload, as well as physiological adaptive hypertrophy, is accompanied by an increase in protein ubiquitination, proteasome subunit expression, and proteasome activity. Importantly, an inhibition of proteasome activity prevents and reverses cardiac hypertrophy and remodelling in vivo. The focus of this review is to provide an update about the mechanisms by which proteasome inhibitors affect cardiac cell growth in adaptive and maladaptive models of cardiac hypertrophy. In the first part, we summarize how the proteasome affects both proteolysis and protein synthesis in a context of cardiac cell growth. In the second part, we show how proteasome inhibition can prevent and reverse cardiac hypertrophy and remodelling in response to different conditions of overload.

Figure 1

Structure of the ubiquitin-proteasome pathway. See text for details. U, ubiquitin. The figure shows the reactions catalysed by E1, E2, and E3 (blue). For the 26S proteasome, the 19S cap (red) is composed of six ATPase subunits (Rpt1–6) and 12 non-ATPase subunits (Rpn1–12), the 20S core is composed of two inner rings made of seven β subunits (blue) and two outer rings containing seven α subunits (green), and the 11S activator (yellow) is composed of three subunits, α, β, and γ.

Figure 2

Transport of denatured proteins to the proteasome by eEF1A. The elongation factor eEF1A binds aminoacyl tRNAs to the A-site of the ribosomes, and it participates in co-translational protein degradation by delivering denatured client proteins to the 19S proteasome. If eEF1A becomes saturated with damaged peptides, it can no longer promote translation. 40S, small ribosome subunit; 60S, large ribosome subunit; AAAAA, poly A tail.

Figure 3

Interference of proteasome inhibitors with cardiac remodelling. During cardiac stress, NF-κB is activated upon removal of IκB, which is phosphorylated by IKK, and degraded by the proteasome. NF-κB activation stimulates the expression of MMPs, leading to cardiac remodelling, increased expression of collagen, alteration in cardiac structure, and increased stress. Inhibition of the proteasome prevents IκB degradation, thereby restraining NF-κB activity.