Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling

Abstract

The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3beta signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3beta signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3beta signaling.

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

“…In contrast, the mRNA and protein levels of Cat S are markedly increased in rats or humans with hypertension-induced heart failure, suggesting that Cat S participates in pathological LV remodeling by mediating ECM degradation in cooperation with the MMPs. Tang et al [22] found that overexpression of cathepsin L inhibits cardiac hypertrophy and fibrosis by blocking Akt/GSK3beta signaling. Blocking the angiotensin II type 1 receptor was reported [20] to attenuate cardiac remodeling and dysfunction by inhibiting the expression and activity of cathepsin.…”

From furless to heartless—unraveling the diverse functions of cathepsin L.

“…These and other transcription factor substrates are also important in the heart. The CTSL-related effects shown by Tang et al [5] remain imperfectly defined. NF-κB could be involved; however, this hypothesis needs to be tested further.…”

“…Tang et al [5], in this issue, pursue variations on this theme further. They overexpressed human CTSL in the mouse heart.…”

“…1. Tang et al [5] presented evidence that the mechanism could be related to nuclear factor kappa B (NF-κB) inhibition by CTSL overexpression.…”

“…Protein kinase B/Akt phosphorylates the two GSK3 isoforms and thereby inhibits their activities. However, as Tang et al [5] point out, the situation is far more complicated. Numerous additional signaling pathways potentially regulate GSK3 activity.…”