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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Signaling

Background:

• Cathepsin B (CTSB) is a lysosomal protease involved in apoptosis and cancer.
• CTSB is present in the heart and has been linked to myocardial infarction.
• Cathepsin L ameliorates cardiac hypertrophy, suggesting a role for CTSB in cardiac remodeling.

Purpose of the Study:

• To investigate the role of Cathepsin B (CTSB) in pressure overload-induced cardiac remodeling.
• To determine if CTSB contributes to pathological cardiac hypertrophy and dysfunction.

Main Methods:

• Utilized in vivo (aortic banding) and in vitro models of cardiac hypertrophy.
• Employed Cathepsin B (CTSB) knockout mouse models.
• Analyzed the activation of TNF-α, ASK1, JNK, and downstream signaling molecules.
• Investigated the effect of JNK inhibitor (SP600125) on cardiomyocyte hypertrophy.

Main Results:

• CTSB expression was upregulated in cardiomyocytes under hypertrophic stimuli.
• CTSB deficiency attenuated cardiac hypertrophy, fibrosis, dysfunction, and apoptosis in response to pressure overload.
• Aortic banding-induced activation of TNF-α, ASK1, JNK, and cytochrome c release was blunted in CTSB knockout mice.
• Angiotensin II-induced cardiomyocyte hypertrophy was reduced by CTSB deficiency.
• JNK inhibition suppressed cardiomyocyte hypertrophy by blocking the ASK1/JNK pathway.

Conclusions:

• CTSB plays a critical role in pressure overload-induced cardiac remodeling.
• CTSB acts as a necessary modulator of hypertrophic response.
• CTSB regulates cardiac remodeling via the TNF-α/ASK1/JNK signaling pathway.