The bitter end: the ubiquitin-proteasome system and cardiac dysfunction.
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.
Patterson
Cam
C
Division of Cardiology and Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126, USA. cpatters@med.unc.edu
Ike
Christopher
C
Willis
Park W
PW
Stouffer
George A
GA
Willis
Monte S
MS
D000818:Animals; D017209:Apoptosis; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex