Sent to Destroy

Abstract

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible due to their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative “specific” mechanisms. The cytosolic receptors p62, NBR, and HDAC6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of “selective autophagy”. Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the cross-talk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Similarly, the expression of NCX‐1, which is regulated by the mitogen‐activated protein kinases P38 and HDAC,41, 42 and mitochondrial apoptosis markers (Bax and BNIP3), which are regulated by the mitogen‐activated protein kinases JNK,12 were increased in the MOD phenotype only. These findings suggest that despite preservation of LVEF (relative to sham), the MOD phenotype had differential activation of signaling pathways and/or degradation systems43 than the CR and MILD phenotypes and similar to that seen in systolic HF.…”

Short Communication Huwe1 as a therapeutic target for neural injury

“…Many cellular processes are regulated by UPS, including protein stability, cell cycle control, DNA repair, transcription, signal transduction, and protein trafficking (Kinyamu et al, 2005;Fasanaro et al, 2010;Willis et al, 2010). In fact, UPS plays a key role in various stress conditions such as ischemia, glutamate toxicity, Alzheimer's disease and Parkinson's disease (Valera et al, 2005;Meller, 2009;Jiang et al, 2010).…”

Nrf2 Deficiency Prevents Reductive Stress Induced Hypertrophic Cardiomyopathy

“…Intracellular oxidative modification of proteins is a key event required for proper ubiquitination and protein degradation. 39,40 Therefore, prevention of PA and pathological cardiac remodelling through quenching chronic RS has potential clinical relevance in the recovery of redox homeostasis and PA dependent hypertrophic cardiomyopathy. Taken together, our results support the conclusion that chronic RS exacerbates PA and causes pathological remodelling, and that a homeostatic redox milieu is necessary and sufficient to prevent pathological PA.…”