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

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

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

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.

Role of Dipeptidyl Peptidase-4 in Atherosclerotic Cardiovascular Disease in Humans and Animals with Chronic Stress.

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase. DPP-4 is upregulated in metabolic and inflammatory cardiovascular disorders. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates, such as glucagon-like peptide-1 (GLP-1). Over the last 10 years, emerging data have demonstrated unexpected roles of DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism. This mini-review focuses on recent novel findings in this field, highlighting a DPP-4-mediated regulation of GLP-1-dependent and -independent signaling pathways as a potential therapeutic molecular target in treatments of chronic psychological stress-related ACVD in humans and animals.

Adaptive immune disorders in hypertension and heart failure: focusing on T-cell subset activation and clinical implications.

: Hypertension is a growing health concern worldwide. Established hypertension is a causative factor of heart failure, which is characterized by increased vascular resistance and intractable uncontrolled blood pressure. Hypertension and heart failure have multiple causes and complex pathophysiology but cellular immunity is thought to contribute to the development of both. Recent studies showed that T cells play critical roles in hypertension and heart failure in humans and animals, with various stimuli leading to the formation of effector T cells that infiltrate the cardiovascular wall. Monocytes/macrophages also accumulate in the cardiovascular wall. Various cytokines (e.g. interleukin-6, interleukin-17, interleukin-10, tumor necrosis factor-α, and interferon-γ) released from immune cells of various subtypes promote vascular senescence and elastic laminal degradation as well as cardiac fibrosis and/or hypertrophy, leading to cardiovascular structural alterations and dysfunction. Recent laboratory evidence has defined a link between inflammation and the immune system in initiation and progression of hypertension and heart failure. Moreover, cross-talk among natural killer cells, adaptive immune cells (T cells and B cells), and innate immune cells (i.e. monocytes, macrophages, neutrophils, and dendritic cells) contributes to end-cardiovasculature damage and dysfunction in hypertension and heart failure. Clinical and experimental studies on the diagnostic potential of T-cell subsets revealed that blood regulatory T cells, CD4 cells, CD8 T cells, and the ratio of CD4 to CD8 T cells show promise as biomarkers of hypertension and heart failure. Therapeutic interventions to suppress activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of cardiovascular failure, including hypertension of heart failure.

Dose rectification of an imbalance between DPP4 and GLP-1 ameliorates chronic stress-related vascular aging and atherosclerosis?

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Dipeptidyl peptidase-4 (DPP-4) exerts many physiological and pharmacological functions by regulating its extremely abundant substrates [eg., glucagon-like peptide-1 (GLP-1), stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, etc.]. Over the past decade, emerging data has revealed unexpected roles for DPP-4 and GLP-1 in intracellular signaling, oxidative stress production, lipid metabolism, cell apoptosis, immune activation, insulin resistance, and inflammation. This mini review focuses on recent findings in this field, highlighting an imbalance between DPP4 and GLP-1 as a potential therapeutic target in the management of vascular aging and atherosclerosis in animals under experimental stress conditions.