Proteotoxicity and Cardiac Dysfunction — Alzheimer’s Disease of the Heart?

Perspective:

The following are 10 points to consider from this review:

1. Misfolded proteins play a central role in the pathophysiology of neurodegenerative diseases like Huntington’s, Parkinson’s, and Alzheimer’s disease. Misfolded proteins have also been shown to play a role in hypertrophic and dilated cardiomyopathies.

2. Cardiomyocytes have limited regenerative potential, so quality control mechanisms for replacing dysfunctional proteins are critical to protect the cell. A balance between protein synthesis, protein folding, and protein turnover is necessary.

3. Newly translated proteins associate with molecular chaperones, which are specialized proteins that stabilize and fold nascent proteins. Chaperones and folding enzymes interact with unfolded nascent proteins to minimize aggregation.

4. The most abundant chaperone protein in the heart, αB-crystallin (CryAB), interacts with desmin. Mutations in CryAB lead to desmin-related cardiomyopathies.

5. Two systems are responsible for the turnover of damaged proteins in the heart: the ubiquitin–proteasome system and the process of autophagy.

6. The ubiquitin–proteasome system is a highly specific, coordinated cascade of enzymes that target specific proteins and label them with multiple ubiquitin molecules, which in turn serve as recognition signals for their subsequent degradation by the proteasome.

7. Autophagy, a less specific process, enhances the degradation of damaged organelles and aggregates of misfolded proteins by placing them in vacuoles that fuse with lysosomes, allowing their contents to be degraded.

8. Failure of autophagy has been associated with heart failure, ischemic heart disease, and chemotherapy-induced cardiomyopathies.

9. Therapies that reduce the accumulation of misfolded proteins, their toxic effects, or both may be helpful in patients with congestive heart failure. Preclinical studies suggest that exercise and drugs such as geranylgeranylacetone may halt progression of heart failure due to misfolded proteins.

10. Despite large increases in the number of patients with chronic congestive heart failure, there have been few innovations in pharmacologic approaches to treat it. This review raises awareness that wear and tear in the heart due to protein misfolding may be a major and targetable contributor to cardiac dysfunction.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Ubiquitin, Myocardial Ischemia, Quality Control, Vacuoles, Desmin, Crystallins, Autophagy, Mutation, Protein Folding, Diterpenes, Proteasome Endopeptidase Complex, Myocytes, Cardiac, Cardiomyopathy, Dilated, Lysosomes, Molecular Chaperones


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