Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice

Abstract

The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) has been observed in proteinopathies, such as desmin-related cardiomyopathy, and implicated in many common diseases, including dilated cardiomyopathy and ischemic heart disease. However, the pathogenic role of PFI has not been established. Here we created inducible Tg mice with cardiomyocyte-restricted overexpression of proteasome 28 subunit α (CR-PA28αOE) to investigate whether upregulation of the 11S proteasome enhances the proteolytic function of the proteasome in mice and, if so, whether the enhancement can rescue a bona fide proteinopathy and protect against ischemia/reperfusion (I/R) injury. We found that CR-PA28αOE did not alter the homeostasis of normal proteins and cardiac function, but did facilitate the degradation of a surrogate misfolded protein in the heart. By breeding mice with CR-PA28αOE with mice representing a well-established model of desmin-related cardiomyopathy, we demonstrated that CR-PA28αOE markedly reduced aberrant protein aggregation. Cardiac hypertrophy was decreased, and the lifespan of the animals was increased. Furthermore, PA28α knockdown promoted, whereas PA28α overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes. Moreover, CR-PA28αOE limited infarct size and prevented postreperfusion cardiac dysfunction in mice with myocardial I/R injury. We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28αOE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury.

Proteostasis in cardiac health and disease

“…Augmentation of PQC might, there fore, have beneficial effects in these forms of cardio myopathies. Indeed, experimental studies have already revealed that induction of proteasomal or autophagic degradation delays the onset of cardiomyopathy in mice with the Cryab R120G mutation [100][101][102] .…”

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

“…In the past 15 years, a missense (R120G) mutation of alpha B-crystallin (CryAB R120G ), a bona fide misfolded protein linked to human disease (60), has been extensively used to study cardiac cytosolic PQC (10,20,(61)(62)(63)(64)(65). Inadequate PQC, as manifested by UPS and ALP functional insufficiency (10,20,61,62,65), has been experimentally demonstrated to play a major pathogenic role in CryAB R120G -induced cardiomyopathy in both cardiomyocyte cultures and transgenic mice (7).…”

“…Inadequate PQC, as manifested by UPS and ALP functional insufficiency (10,20,61,62,65), has been experimentally demonstrated to play a major pathogenic role in CryAB R120G -induced cardiomyopathy in both cardiomyocyte cultures and transgenic mice (7). Notably, a reductive stress hypothesis had been proposed by Rajasekaran and colleague to explain pertubed PQC and resultant cardiac pathology caused by increased expresion of a misfolded cytosolic chaperone protein, based on their studies on a transgenic mouse model of cardiac overexpression of a human CryAB R120G (hCryAB R120G ) (66).…”

“…Hence, here we propose an alternative model which takes the findings by Kannan et al into consideration along with most, if not all, other important findings from studying a similar mCryAB R120G mouse model. First, although both proteasome activity and macroautophagy are adaptively upregulated in CryAB R120G overexpressing hearts (62,67), these upregulations are inadequate and both proteasome functional insufficiency and ALP insufficiency have been demonstrated to play an essential role in mCryAB R120G -based cardiomyopathy (10,65). Second, the ALP insufficiency can in turn impede the degradation of ubiquitinated proteins by proteasome via accumulation of an ALP substrate protein p62 (22,23).…”

“…Therefore, it is not surprising that dysregulation of UPS components and the overall UPS-proteolytic function has been implicated in the pathogenesis of numerous human diseases including a large subset of cardiovascular diseases. For example, proteasome functional insufficiency is implicated in the majority of failing human hearts and has been experimentally demonstrated to be a major pathogenic factor in not only cardiac conformational disease but ischemia-reperfusion injury (7,9,10). Hence, it is important to better understand how the UPS, especially proteasome function, is regulated in cardiac health and disease.…”