Sterile Inflammation and Degradation Systems in Heart Failure

Abstract

In most patients with chronic heart failure (HF), levels of circulating cytokines are elevated and the elevated cytokine levels correlate with the severity of HF and prognosis. Various stresses induce subcellular component abnormalities, such as mitochondrial damage. Damaged mitochondria induce accumulation of reactive oxygen species and apoptogenic proteins, and subcellular inflammation. The vicious cycle of subcellular component abnormalities, inflammatory cell infiltration and neurohumoral activation induces cardiomyocyte injury and death, and cardiac fibrosis, resulting in cardiac dysfunction and HF. Quality control mechanisms at both the protein and organelle levels, such as elimination of apoptogenic proteins and damaged mitochondria, maintain cellular homeostasis. An imbalance between protein synthesis and degradation is likely to result in cellular dysfunction and disease. Three major protein degradation systems have been identified, namely the cysteine protease system, autophagy, and the ubiquitin proteasome system. Autophagy was initially believed to be a non-selective process. However, recent studies have described the process of selective mitochondrial autophagy, known as mitophagy. Elimination of damaged mitochondria by autophagy is important for maintenance of cellular homeostasis. DNA and RNA degradation systems also play a critical role in regulating inflammation and maintaining cellular homeostasis mediated by damaged DNA clearance and post-transcriptional regulation, respectively. This review discusses some recent advances in understanding the role of sterile inflammation and degradation systems in HF.

Metabolomic Analysis in Heart Failure

“…Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approach cannot describe the whole picture, but cardiac metabolism is one of the most critical factors. 7 The heart is a unique organ destined to work continuously as a "pump" supplying blood to the body.…”

The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure

“…The link between HF and inflammation was first recognized in 1990 by Levine et al, who reported elevated levels of tumor necrosis factor α (TNF α ) in patients with HF with reduced ejection fraction [ 8 ]. Numerous studies have demonstrated that patients with HF exhibited raised circulating levels of other inflammatory cytokines, such as interleukin- (IL-) 1 β and IL-6, and several chemokines, including monocyte chemoattractant peptide- (MCP-) 1, IL-8, macrophage inflammatory protein- (MIP-) 1 α , and galectin-3 [ 9 – 14 ]. These data suggest that increased systemic levels of inflammatory cytokines in patients with HF may reflect important pathogenic mechanisms.…”

Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes

“…Conversely, enhancement of cardiac proteasome proteolytic function plays a protective role against the pathophysiology of proteinopathy and ischemia-reperfusion (IR) injury in mice (Li et al, 2011). Furthermore, accumulation of polyubiquitinated substrates has been observed in the heart tissue of patients with cardiac diseases such as cardiomyopathy and heart failure (Nishida and Otsu, 2017).…”