Article

The ubiquitin-proteasome system in cardiac proteinopathy: A quality control perspective

Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Lee Medical Building, 414 E Clark Street, Vermillion, SD 57069, USA.
Cardiovascular Research (Impact Factor: 5.94). 09/2009; 85(2):253-62. DOI: 10.1093/cvr/cvp287
Source: PubMed

ABSTRACT

Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure.

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Available from: Xuejun Wang, Jun 03, 2015
    • "When this system is functionally compromised or overstrained, ubiquitinated protein accumulate in the cell. This pathophysiological process, termed proteasomal functional insufficiency (PFI), has been shown to be an important factor in the pathogenesis of desmin-related cardiomyopathies[44]and other cardiac muscle diseases[45]. In turn, stimulation of proteasome activity can be used to attenuate the phenotype of DRC[25]. "
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    ABSTRACT: The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes and has been recognized as a hot spot for cardiomyopathy. We have previously identified Myozap as a novel cardiac-enriched ID protein, which interacts with several other ID proteins and is involved in RhoA/SRF-signaling in vitro. To now study its potential role in vivo we generated a mouse model with cardiac overexpression of Myozap. Transgenic (Tg) mice developed cardiomyopathy with hypertrophy and LV dilation. Consistently, these mice displayed upregulation of the hypertrophy-associated and SRF-dependent gene expression. Pressure overload (transverse aortic constriction, TAC) caused exaggerated cardiac hypertrophy, further loss of contractility and LV dilation. Similarly, a physiological stimulus (voluntary running) also led to significant LV dysfunction. On the ultrastructural level, Myozap-Tg mouse hearts exhibited massive protein aggregates composed of Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the alterations observed in desmin-related cardiomyopathy. Interestingly, desmin was not detectable in the aggregates, yet was largely displaced from the ID. Molecular analyses revealed induction of autophagy and dysregulation of the unfolded protein response (UPR), associated with apoptosis. Taken together, cardiac overexpression of Myozap leads to cardiomyopathy, mediated, at least in part by induction of Rho-dependent SRF signaling in vivo. Surprisingly, this phenotype was also accompanied by protein aggregates in cardiomyocytes, UPR alteration, accelerated autophagy and apoptosis. Thus, this mouse model may also offer additional insight into the pathogenesis of protein aggregate-associated cardiomyopathies and represents a new candidate gene itself.
    No preview · Article · Jul 2014 · Journal of Molecular and Cellular Cardiology
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    • "Proteinopathies are diseases that are characterized by protein misfolding and aggregation, including desmin-related cardiomyopathy (DRC) [280] [281]. Proteasome function insufficiency is observed in a variety of heart diseases [282] [283] in animals, i.e. myocardial ischemia/ reperfusion (I/R) injury and pressure overload-induced cardiomyopathy [281] [284] [285], as well as in humans, i.e. hypertrophic or dilated cardiomyopathy [283] [286]. Cardiomyocyte-restricted overexpression of the proteasome 28 subunit α (CR-PA28αOE) in mice caused augmentation of cardiac UPS proteolytic function. "
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    • "Insufficient proteasomal proteolysis is being recognized as an important pathogenic factor to various forms of cardiac disease [110] [111]. Although CSN has been long viewed as a UPS regulator due to its ability to control CRL activity and its structural similarity to the 19S proteasome lid [112], the in vivo experimental evidence is still lacking. "
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