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Atherosclerosis (AS) is a chronic inflammatory disease involving cell death and inflammatory responses. Pyroptosis, a newly discovered pro-inflammatory programmed cell death process, exacerbates inflammatory responses. However, the roles of cathepsin B (CTSB) in pyroptosis and AS remain unclear. To gain further insight, we fed ApoE-/- mice a high-fat diet to investigate the effects and mechanisms of CTSB overexpression and silencing on AS. We also explored the specific role of CTSB in vascular smooth muscle cells (VSMCs) in vitro. The study revealed that high-fat diet led to the formation of AS plaques, and CTSB was found to increase the AS plaque lesion area. Immunohistochemical and TUNEL/caspase-1 staining revealed the existence of pyroptosis in atherosclerotic plaques, particularly in VSMCs. In vitro studies, including Hoechst 33342/propidium iodide staining, a lactate dehydrogenase (LDH) release assay, detection of protein indicators of pyroptosis, and detection of interleukin-1β (IL-1β) in cell culture medium, demonstrated that oxidized low-density lipoprotein (ox-LDL) induced VSMC pyroptosis. Additionally, CTSB promoted VSMC pyroptosis. Ox-LDL increased the expression of CTSB, which in turn activated the NOD-like receptor protein 3 (NLRP3) inflammasome and promoted NLRP3 expression by facilitating nuclear factor kappa B (NF-κB) p65 nuclear translocation. This effect could be attenuated by the NF-κB inhibitor SN50. Our research found that CTSB not only promotes VSMC pyroptosis by activating the NLRP3 inflammasome, but also increases the expression of NLRP3. [ABSTRACT FROM AUTHOR]

[Display omitted] Cardiac fibrosis is pivotal in the progression of numerous cardiovascular diseases. This phenomenon is hallmarked by an excessive deposition of ECM protein secreted by myofibroblasts, leading to increased myocardial stiffness. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein-converting enzyme family. It has emerged as a viable therapeutic target for reducing plasma low-density lipoprotein cholesterol. However, the exact mechanism via which PCSK9 impacts cardiac fibrosis remains unclear. In the present research, an increase in circulating PCSK9 protein levels was observed in individuals with myocardial infarction and rat models of myocardial infarction. Moreover, the inhibition of circulating PCSK9 in rats was found to reduce post-infarction fibrosis. In vitro experiments further demonstrated that overexpression of PCSK9 or stimulation by extracellular PCSK9 recombinant protein enhanced the transformation of cardiac fibroblasts to myofibroblasts. This process also elevated collagen Ⅰ, and Ⅲ, as well as α-SMA protein levels. However, these effects were countered when co-incubated with the STAT3 inhibitor S3I-201. This study suggests that PCSK9 may function as a novel regulator of myocardial fibrosis, primarily via the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]