The Bitter End

Abstract

Abstract-Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process.Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…Specifically, the NBD peptide prevents the IKKgamma (NEMO) from forming its interaction with IKKβ by competitive inhibition [45]. This mechanism is distinct from other NF-κB inhibitor strategies, such as proteasome inhibition, because it doesn't affect the necessary basal proteasome activity vital to protein quality control [47,50,71,72]. This peptide has been used successfully in diminishing inflammatory responses in several animal models of disease, including inflammatory bowel disease [2,18,21,36,55].…”

The ubiquitin proteasome system in human cardiomyopathies and heart failure

“…A few of likely many cardiac E3s identified to date include atrogin-1, the muscle ring finger (MuRF) family (MuRF1, MuRF2, and MuRF3), carboxyl terminus of heat shock protein 70-interacting protein, and murine double minute 2 (100). In cellular and animal models, these particular ligases, along with their target substrates, have been shown to play an important role in response to various pathological stimuli in the heart, including ischemia, apoptosis, and cardiac hypertrophy (62,97,99).…”

Differential Effect of the Protein Synthesis Inhibitors Puromycin and Cycloheximide on Vascular Smooth Muscle Cell Viability

“…Because puromycin did not inhibit the proteasome, accumulation of polyubiquitinated proteins may reflect an overwhelming synthesis of misfolded proteins that cannot be degraded by the proteasome. These misfolded and/or truncated proteins potently activate apoptotic pathways, and they are prone to aggregation or other gain-of-function toxicities that may damage the cell (Hashimoto et al, 2003;Patterson et al, 2007).…”