Protein Misfolding in Cardiac Disease

lthough mortality from some types of cardiovascular disease is decreasing, future therapies aimed at treating underlying mechanisms may improve clinical outcomes yet further.Based on recent discoveries, it is becoming apparent that defects in intracellular protein quality and age-related impairments in protein homeostasis, or proteostasis, are contributing factors in many forms of cardiac disease.In the heart, such impairments can lead to cardiac myocyte dysfunction and eventually cell death, a particularly important problem given that cardiac muscle exhibits limited regenerative potential.Now, exciting efforts are focused on developing therapies targeting defective proteostasis, some of which have transitioned from preclinical proof-of-concept studies into clinical practice. WHAT IS PROTEOSTASIS, WHAT KEEPS IT BALANCED, AND WHY IS THIS BALANCE IMPORTANT?Protein quality can be compromised by genetically encoded mutations, and by mistakes in transcription or translation, resulting in errors as small as 1 amino acid substitution.This, in turn, can disrupt normal protein folding, intracellular translocation, or function.In addition, disease-related stresses, such as ischemia, can trigger protein misfolding, and unfolding of proteins that were once properly folded and functional, as well.Exposed hydrophobic regions of misfolded proteins bind to similar regions in nearby proteins, leading to inappropriate associations and protein aggregation.The aggregating species can continue to bind exposed hydrophobic regions of neighboring proteins and thus have the potential to form stable, both soluble and insoluble, nonfunctional structures.These protein aggregates interfere with normal cell function in numerous ways, including by disrupting protein complexes, interacting with lipids and membranes, and possibly interfering with contractile function.Protein aggregates can recruit and sequester components of the proteostasis machinery, including chaperones and elements of the ubiquitin and proteasome machinery, presumably to aid in the clearance of the aggregated species, facilitating dysregulated proteostasis and chronic activation of stress responses, which can result in cell death. 1 Moreover, whereas most misfolded proteins are prevented from transiting out of the cell, some can be secreted from their cell of origin and deposited in distant tissues.This results in deleterious functional consequences deriving from pathogenic proteins clustering on plasma membranes, altering lipid bilayer fluidity, membrane architecture, and the normal distribution of membrane proteins.A central tenet of cell biology is that protein synthesis takes place where the ribosomes are located.This means that, in eukaryotic cells, protein synthesis occurs in the cytoplasm, and on the ribosome-studded rough endoplasmic reticulum (synthesis of secreted and membrane proteins) and in mitochondria, as well (Figure A).