Cytokine-induced oxidative stress in cardiac inflammation and heart failure-how the ubiquitin proteasome system targets this vicious cycle

Abstract

The ubiquitin proteasome system (UPS) is critical for the regulation of many intracellular processes necessary for cell function and survival. The absolute requirement of the UPS for the maintenance of protein homeostasis and thereby for the regulation of protein quality control is reflected by the fact that deviation of proteasome function from the norm was reported in cardiovascular pathologies. Inflammation is a major factor contributing to cardiac pathology. Herein, cytokines induce protein translation and the production of free radicals, thereby challenging the cellular protein equilibrium. Here, we discuss current knowledge on the mechanisms of UPS-functional adaptation in response to oxidative stress in cardiac inflammation. The increasing pool of oxidant-damaged degradation-prone proteins in cardiac pathology accounts for the need for enhanced protein turnover by the UPS. This process is accomplished by an up-regulation of the ubiquitylation machinery and the induction of immunoproteasomes. Thereby, the inflamed heart muscle is cleared from accumulating misfolded proteins. Current advances on immunoproteasome-specific inhibitors in this field question the impact of the proteasome as a therapeutic target in heart failure.

Keywords: cytokines; inflammation; oxidative stress; proteasome; protein quality control.

Figure 1

Myocardial injury induces reactive oxygen species (ROS) and reactive nitrogen species (RNS) via the activity of NADPH-oxidase (NOX) and nitric oxide synthase (NOS). Thereby, endogenous material being referred to as danger-associated molecular patterns (DAMPs) is released. DAMPs activate membrane-bound Toll-like receptors (TLRs) and cytoplasmatic Nucleotide-binding/oligomerization domain-like receptors (NLRs). TLR and NLR-signaling results in cytokine and chemokine release. Chemokines attract inflammatory cells and thereby facilitate tissue repair. Upon activation of the mammalian target of rapamycin (mTOR)-pathway, cytokines activate the cellular translation machinery giving rise to an increased pool of misfolded, damaged proteins known as defective ribosomal products (DRIPs). These nascent proteins are prone to be further modified by ROS/RNS eventually leading to an imbalance in the protein homeostasis with a surplus of misfolded, oxidant-damaged proteins in the cell. Here, regulatory components within the proteasomes take action—in inflammation, immunoproteasomes with increased proteolytic activity are formed that ensure the timely degradation of these inherently toxic protein aggregates. However, whenever the immunoproteasome is dysfunctional or not properly assembled, proteotoxic aggregates accumulate thereby promoting cell death. This in turn creates a vicious cycle eventually potentiating cardiac remodeling and heart failure.