Heart disease remains the number one cause of death in the United States, and the evolution of treatments for heart attacks has led to a significant reduction in the number of cardiac fatalities. Today nearly 90% of patients hospitalized for a heart attack will not only survive, but return to their normal activities within weeks – if not sooner. Yet these advances have resulted in a paradoxical situation; a burgeoning burden of patients with heart failure.

Current treatments for heart attacks and heart failures use therapies that target the rennin-angiotensin-aldosterone system; i.e. beta-blockers, and calcium channel blockers that reduce blood pressure, heart rate, and cardiac contractility (strength in which the heart pumps). However, these therapies are limited in their long-term effects on heart failure outcomes. The time has come for us to identify new ways of strengthening the heart in heart failure.

After a heart attack, for example, the routine maintenance of protein folding in heart failure is disturbed. Like parts in an excessively used machine, the proteins in a cell wear out. And recognizing these proteins to degrade them is part of the normal processes cells have developed to maintain their “fitness”. Recent studies have illustrated that misfolded proteins accumulate in humans with heart failure, and that having misfolded proteins, like those found in Huntington’s disease, expressed in heart cells (cardiomyocytes) directly causes heart failure in healthy hearts.

The accumulation of these worn proteins, which are often characterized as misfolded, is the basis of some of the most devastating brain diseases we have. These include neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. But these misfolded proteins appear to occur in heart failure. Experimentally, when misfolded proteins are expressed in the heart, they can actually CAUSE heart failure, a concept that may allow development of new therapies (Willis & Patterson, 2013).

This is exciting news, given the headstart of treatments for Alzheimer’s disease. Clinical trials targeting misfolded proteins in development for neurodegenerative diseases, also suggests that new ways to treat heart failure may be possible, although currently untested.

The heart depends upon the coordination of a complex network of communicating cells to act as a single contractile apparatus. For optimal cardiomyocyte function, there must be a critical balance among protein synthesis, protein folding, and protein turnover.

However, cardiomyocytes are limited when it comes to overseeing the quality control of proteins once they undergo excessive stress, like that occurring with heart attacks, poor diet, obesity, and lack of exercise. Molecular chaperones regulate protein aggregation and misfolding, essential for preventing cell death as a result of unfold or aggregated proteins. But they are limited in their ability when overwhelmed.

To do their job, molecular chaperones need to work in concert with the unbiquitin-proteasome system.

A unique process begins when sarcomeric proteins become misfolded owing to routine stresses such as mechanical damage and oxidative stress, molecular chaperones attempt to refold the damaged proteins; however, if this fails, the molecular chaperones send their problematic proteins over to the ubiquitin ligase, which then ubiquitinylate the damaged proteins.

If the ubiquitin-proteasome system cannot meet the proteolytic demands of the cell because of an overload of misfolded proteins or impairment of the proteasome, autophagy kicks in.

Cellular death – known as proteotoxicity, has been implicated in the pathogenesis of Alzheimer’s disease and other proteinpathies like Huntington’s and Parkinson’s disease (Cheng et al., 2013).

The accumulation of misfolded proteins and subsequent proteotoxicity crucial to the pathophysiology of neurodegenerative diseases parallels new findings in heart failure pathophysiology. Recent studies in the CryAB mouse model – which was found to have a rare but well-defined genetic disorder that increased susceptibility to misfolded proteins – demonstrated that defects in protein folding alone, could lead to heart failure (Sanbe et al., 2004).

Therapeutic “protein rescue” studies by Dr. Michael Conn and his colleagues at the Oregon Health Sciences University and Texas Tech Health Sciences University have developed “pharmacoperone” drugs that are capable of unfolding proteins in animals, and might very well hold the key for rehabilitating misfolded proteins in humans.

This new research indicates that we could develop novel pharmalogical therapies that would target the misfolded proteins in the heart, and by doing so right the imbalance of heart disease continuing to be the number one killer across the world.

About Monte S. Willis

Monte S. Willis, MD, PhD, is associate professor at the Department of Pathology and Laboratory Medicine, Director of Campus Health Services Laboratory, and Director of the McLendon Clinical Laboratories at the University of North Carolina in Chapel Hill, where he leads a research team studying the role of the ubiquitin proteasome system in metabolism and the pathophysiology of cardiac disease, teaches in the School of Medicine and Graduate School, and is currently completing his MBA at Kenan-Flagler Business School. His book, Cellular and Molecular Pathobiology of Cardiovascualar Disease, that he authored with Dr. Jonathan Homeister and Dr. James Stone, published earlier this year.

References

Cheng, B., Gong, H., Xiao, H., Petersen, R. B., Zheng, L., & Huang, K. (2013). Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases. Biochim Biophys Acta, 1830(10), 4860-4871. doi: 10.1016/j.bbagen.2013.06.029

Sanbe, A., Osinska, H., Saffitz, J. E., Glabe, C. G., Kayed, R., Maloyan, A., & Robbins, J. (2004). Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc Natl Acad Sci U S A, 101(27), 10132-10136. doi: 10.1073/pnas.0401900101

Willis, M. S., & Patterson, C. (2013). Proteotoxicity and cardiac dysfunction–Alzheimer’s disease of the heart? N Engl J Med, 368(5), 455-464. doi: 10.1056/NEJMra1106180

© Monte S. Willis 2014