Cathepsin‐L Ameliorates Cardiac Hypertrophy Through Activation of the Autophagy–Lysosomal Dependent Protein Processing Pathways

Abstract

BackgroundAutophagy is critical in the maintenance of cellular protein quality control, the final step of which involves the fusion of autophagosomes with lysosomes. Cathepsin‐L (CTSL) is a key member of the lysosomal protease family that is expressed in the murine and human heart, and it may play an important role in protein turnover. We hypothesized that CTSL is important in regulating protein processing in the heart, particularly under pathological stress.Methods and ResultsPhenylephrine‐induced cardiac hypertrophy in vitro was more pronounced in CTSL‐deficient neonatal cardiomyocytes than in in controls. This was accompanied by a significant accumulation of autophagosomes, increased levels of ubiquitin‐conjugated protein, as well as impaired protein degradation and decreased cell viability. These effects were partially rescued with CTSL1 replacement via adeno‐associated virus–mediated gene transfer. In the in vivo murine model of aortic banding (AB), a deficiency in CTSL markedly exacerbated cardiac hypertrophy, worsened cardiac function, and increased mortality. Ctsl−/− AB mice demonstrated significantly decreased lysosomal activity and increased sarcomere‐associated protein aggregation. Homeostasis of the endoplasmic reticulum was also altered by CTSL deficiency, with increases in Bip and GRP94 proteins, accompanied by increased ubiquitin–proteasome system activity and higher levels of ubiquitinated proteins in response to AB. These changes ultimately led to a decrease in cellular ATP production, enhanced oxidative stress, and increased cellular apoptosis.ConclusionsLysosomal CTSL attenuates cardiac hypertrophy and preserves cardiac function through facilitation of autophagy and proteasomal protein processing.

SCCA1/SERPINB3 Promotes Oncogenesis and Epithelial–Mesenchymal Transition via the Unfolded Protein Response and IL6 Signaling

“…We have previously reported that expression of SCCA1 leads to a suppression of both lysosomal and proteasomal protein turnover, in a manner that requires its protease inhibitory activity (13). Although the precise mechanism underlying this SCCA1-mediated blockade of protein turnover remains to be determined, our finding is in line with a recent report that the cathepsin L-deficient cells display impaired lysosomal turnover, accumulation of ubiquitinated proteins and protein aggregates, and disrupted ER homeostasis (45). It is conceivable that the blockade of protein turnover can lead to UPR, which we show here promotes pro-tumorigenic IL-6 production.…”

Effects of intermittent exercise on biomarkers of cardiovascular risk in night shift workers

“…If this system is compromised, impaired protein degradation and abnormal protein accumulation may result in not only cellular dysfunction but also organ failure including cardiomyopathy [17]. The participants in the present study had higher levels of CatL than patients with cardiovascular disease [18], and higher levels of CatS than those reported by Job et al [19].…”

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

“…Previous studies have demonstrated that cathepsins are essential for both cardiomyocyte apoptosis (32) and extracellular matrix balance (22a, 29). Further studies have revealed increased cathepsin activity in both hypertrophic and failing hearts (8,31) and showed that cathepsins are regulated under these pathological conditions. CTSB (GenBank Accession No.…”