Overview of multifunctional cysteinyl cathepsins in atherosclerosis-based cardiovascular disease: from insights into molecular functions to clinical implications

Abstract

Cysteinyl cathepsins (CTSs) are widely known to have a proteolysis function that mediates recycling of unwanted proteins in endosomes and lysosomes, and investigation of CTSs has greatly improved with advances in live-imaging techniques both in vivo and in vitro, leading to three key findings. (1) CTSs are relocated from the lysosomes to other cellular spaces (i.e., cytosol, nucleus, nuclear membrane, plasma membrane, and extracellular milieu). (2) In addition to acidic cellular compartments, CTSs also exert biological activity in neutral environments. (3) CTSs also exert multiple nontraditional functions in, for example, extracellular matrix metabolism, cell signaling transduction, protein processing/trafficking, and cellular events. Various stimuli regulate the expression and activities of CTSs in vivo and vitro—e.g., inflammatory cytokines, oxidative stress, neurohormones, and growth factors. Accumulating evidence has confirmed the participation of CTSs in vascular diseases characterized by atherosclerosis, plaque rupture, thrombosis, calcification, aneurysm, restenosis/in-stent-restenosis, and neovasel formation. Circulating and tissue CTSs are promising as biomarkers and as a diagnostic imaging tool in patients with atherosclerosis-based cardiovascular disease (ACVD), and pharmacological interventions with their specific and non-specific inhibitors, and cardiovascular drugs might have potential for the therapeutic targeting of CTSs in animals. This review focuses on the update findings on CTS biology and the involvement of CTSs in the initiation and progression of ACVD and discusses the potential use of CTSs as biomarkers and small-molecule targets to prevent deleterious nontraditional functions in ACVD.

Leveraging the transcriptome to further our understanding of GWAS findings: eQTLs associated with genes related to LDL and LDL subclasses, in a cohort of African Americans

“…The broader group of genes discussed, including CTSW and STAB1, have been linked to lipid processing and cardiovascular health. For example, CTSW has been studied for its role in HDL cholesterol metabolism and its potential impact on atherosclerosis ( Cheng et al, 2023 ), while STAB1 has been implicated in the clearance of atherogenic lipoproteins ( Verwilligen et al, 2022 ). These associations reinforce the systemic nature of blood as a reflection of lipid metabolic health.…”

Dipeptidyl peptidase‐4 disturbs adipocyte differentiation via the negative regulation of the glucagon‐like peptide‐1/adiponectin‐cathepsin K axis in mice under chronic stress conditions

“…The ability of chronic stress to enhance CTSK expression and activity probably contributed to adipose dysfunction mice under our condi-A recent comprehensive review documented the role cysteinyl cathepsins in metabolic cardiovascular disease. 22 Cathepsins function as modulators of cellular events (e.g., migration, proliferation, apoptosis) in various cell lines, and this modulation is dependent on the proteolytic and nonproteolytic functions of the respective cells. 43 It was reported that CTSL activity leads to an enhancement of human and murine pre-adipocyte lipid accumulation and adipogenesis by modulating fibronectin degradation.…”

“…Cysteine protease cathepsins were originally found to be localized to lysosomes and endosomes in humans and animals. 22 The main physiological function of cathepsins is to break down unwanted intracellular or endocytic proteins, but cathepsins also play an important role in pathological processes by regulating inflammation and immune responses through extracellular matrix remodeling, leukocyte recruitment, and cell adhesion. 23,24 Cathepsin K and DPP4 +/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/ or morphological alterations.…”

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model

“…Exposure to CPS is also a comparatively intractable risk factor for thrombotic cardiocerebrovascular diseases (TCVDs) [ 5 – 9 ]. A 2023 review highlighted the close relationship between chronic stress and the prothrombotic state and thrombus formation in animal models and humans with TCVDs [ 10 ].…”