Cathepsin-L ameliorates cardiac hypertrophy through activation of the autophagy-lysosomal dependent protein processing pathways.

Abstract

BACKGROUND:

Autophagy 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 RESULTS:

Phenylephrine-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.

CONCLUSIONS:

Lysosomal CTSL attenuates cardiac hypertrophy and preserves cardiac function through facilitation of autophagy and proteasomal protein processing.

• Authors: Mei Sun, Maral Ouzounian, Geoffrey de Couto, Manyin Chen, Ran Yan, Masahiro Fukuoka, Guohua Li, Mark Moon, Youan Liu, Anthony Gramolini, George J Wells, Peter P Liu
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 2 Issue 2 Pg. e000191 (Apr 22 2013) ISSN: 2047-9980 [Electronic] England
• PMID: 23608608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Membrane Glycoproteins
• Ubiquitinated Proteins
• endoplasmin
• Ubiquitin-Protein Ligase Complexes
• Cathepsin L
• Ctsl protein, mouse

Topics

• Animals
• Apoptosis (physiology)
• Autophagy (physiology)
• Cardiomegaly (enzymology, metabolism, physiopathology)
• Cathepsin L (genetics, physiology)
• Cell Survival
• Cells, Cultured
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Enzyme Assays
• Heat-Shock Proteins (metabolism)
• Lysosomes (physiology)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Myocytes, Cardiac (enzymology, metabolism, physiology)
• Oxidative Stress (physiology)
• Phagosomes (physiology)
• Protein Processing, Post-Translational (physiology)
• Proteolysis
• Ubiquitin-Protein Ligase Complexes (metabolism)
• Ubiquitinated Proteins (metabolism)
• Ventricular Remodeling (physiology)