Proteostasis in cardiac health and disease

Abstract

The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

“…Although there is only a trend towards an increase in HSPA5 expression in patients with AF, diminished protein synthesis or enhanced degradation, by either the proteasome or autophagy, or exhaustion of the protein levels may be the underlying cause . There is ongoing debate about whether autophagy plays a beneficial or detrimental role in cardiac diseases . Excessive autophagy contributed to age‐related cardiac disease development, including heart failure, hypertension‐induced cardiac diseases, mitral regurgitation, and diabetic cardiomyopathy .…”

Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes

“…Adequate protein turnover is essential for cardiac homeostasis [13]. Different protein quality control mechanisms are involved in the maintenance of protein homeostasis, including molecular chaperones and the autophagy pathway [14].…”

In search for novel functions of adenosine 5′-triphosphate (ATP) in the heart

“…Furthermore, it has been shown that alterations in the proteostasis of cardiomyocytes may play an important role in the development of cardiovascular diseases. 3 Accordingly, several studies have provided evidence for an important role of misfolded proteins in the pathophysiology of heart failure, cardiac hypertrophy, dilated and ischaemic cardiomyopathies, and atrial fibrillation. [4][5][6][7][8][9] Prevailing theories of impaired protein homeostasis mainly focus on disturbances of the fine-tuned balance of cellular production, folding, and degradation of proteins.…”

“…Cellular accumulation of protein aggregates has been observed in cardiomyocytes from patients with idiopathic dilated or hypertrophic cardiomyopathy, heart failure, and ischaemic heart disease. 3 Since aggregated proteins may become toxic, damage the cell structure and impair cellular functions, it is very likely that protein aggregates play an important pathophysiological role. In addition, local ATP concentrations may be required to stabilize protein domains containing hydrophobic surfaces, thereby ensuring proper protein-protein interactions.…”

“…The intracellular amount of ATP declines with ageing or impaired mitochondrial oxidative phosphorylation. 2,3 Both, ageing and impaired energy supply are major determinants of cardiovascular diseases such as heart failure, cardiac hypertrophy, dilated and ischaemic cardiomyopathies, and atrial fibrillation. [14][15][16] According to the recent finding by Patel et al, 1 reduced ATP levels may not only play a major role in impaired energy supply but also in disrupted cellular protein homeostasis.…”