Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease characterized by extensive arterial wall matrix protein degradation. Cysteine protease cathepsins play a pivotal role in ...extracellular matrix (ECM) remodeling and have been implicated in the development and progression of atherosclerosis-based cardiovascular diseases. An imbalance in expression between cathepsins (such as cathepsins S, K, L, C) and their inhibitor cystatin C may favor proteolysis of ECM in the pathogenesis of cardiovascular disease such as atherosclerosis, aneurysm formation, restenosis, and neovascularization. New insights into cathepsin functions have been made possible by the generation of knockout mice and by the application of specific inhibitors. Inflammatory cytokines regulate the expression and activities of cathepsins in cultured vascular cells and macrophages. In addition, evaluations of the possibility of cathepsins as a diagnostic tool revealed that the circulating levels of cathepsin S, K, and L, and their endogenous inhibitor cystatin C could be promising biomarkers in the diagnosis of coronary artery disease, aneurysm, adiposity, peripheral arterial disease, and coronary artery calcification. In this review, we summarize the available information regarding the mechanistic contributions of cathepsins to ASCVD.
Dipeptidyl peptidase IV (DPP-IV) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase and transmits intracellular signals through a small intracellular tail. DPP-IV exists ...in human blood in a soluble form, and truncates a large number of peptide hormones, chemokines, cytokines, and growth factors in vitro and in vivo. DPP-IV has gained considerable interest as a therapeutic target, and a variety of DPP-IV inhibitors that prolong the insulinotropic effects of glucagon-like peptide-1 (GLP-1) are widely used in clinical settings as antidiabetic drugs. Indeed, DPP-IV is upregulated in proinflammatory states, including obesity and cardiovascular disease with and without diabetes mellitus. Consistent with this maladaptive role, DPP-IV inhibitors seem to exert a protective role in cardiovascular disease. In addition to their GLP-1-dependent vascular protective actions, DPP-IV inhibitors exhibit GLP-1-independent beneficial effects on angiogenesis/neovascularization via several signaling pathways (e.g., stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, vascular endothelial growth factor-A/endothelial nitric oxide synthase, etc.). This review focuses on recent findings in this field, highlighting the role of DPP-IV in therapeutic angiogenesis/neovascularization in ischemic heart disease and peripheral artery disease.
Atherosclerosis is a serious public health concern. Excessive inflammatory responses of vascular cells are considered a pivotal pathogenesis mechanism underlying atherosclerosis development. It is ...known that Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signalling plays an important role in atherosclerosis progression. Protein inhibitor of activated STAT3 (PIAS3) is the key negative regulator of JAK/STAT3 signalling. However, its effect on atherogenesis is unknown. Here, we observed that PIAS3 levels are reduced in atherosclerotic lesions and that PIAS3 expression decreases in conjunction with increases in interleukin-6 expression and atherosclerosis severity. Oxidized low-density lipoprotein (ox-LDL), an atherogenic stimulus, reduced PIAS3 expression, an effect that may be attributed to nitric oxide synthesis upregulation. In turn, PIAS3 overexpression effectively suppressed ox-LDL-induced inflammation, lipid accumulation and vascular smooth muscle cell proliferation. These results indicate that PIAS3 is a critical repressor of atherosclerosis progression. The findings of this study have contributed to our understanding on the pathogenesis of atherosclerosis and have provided us with a potential target through which we can inhibit atherosclerosis-related cellular responses.
Cathepsin L (CatL) is a potent collagenase involved in atherosclerotic vascular remodeling and dysfunction in animals and humans. This study investigated the hypothesis that plasma CatL is associated ...with the prevalence of coronary artery disease (CAD). Between February May 2011 and January 2013, 206 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. Age-matched subjects (n = 215) served as controls. Plasma CatL and high-sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher plasma CatL levels compared to the controls (1.4 ± 0.4 versus 0.4 ± 0.2 ng/mL, P < 0.001), and the patients with acute coronary syndrome had significantly higher plasma CatL levels compared to those with stable angina pectoris (1.7 ± 0.7 versus 0.8 ± 0.4 ng/mL, P < 0.01). Linear regression analysis showed that overall, the plasma CatL levels were inversely correlated with the high-density lipoprotein levels (r = −0.32, P < 0.01) and positively with hs-CRP levels (r = 0.35, P < 0.01). Multiple logistic regression analyses shows that cathepsin L levels were independent predictors of CAD (add ratio, 1.8; 95% CI, 1.2 to 2.1; P < 0.01). These data demonstrated that increased levels of plasma CatL are closely associated with the presence of CAD and that circulating CatL serves as a useful biomarker for CAD.
Dipeptidyl peptidase-4 (DPP4) is one of the most potent mammalian serine proteases participated in the pathogenesis of subclinical atherosclerosis. Here we investigated whether the plasma soluble ...form of DPP4 is associated with the prevalence of coronary artery disease (CAD) with and without diabetes mellitus (DM). A cross-sectional study was conducted of 496 aged 26-81 years with (n = 362) and without (n = 134) CAD. Plasma DPP4 activity, high sensitive C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein levels were measured. The coronary atherosclerotic plaques were evaluated by coronary angiography. The CAD patients with (n = 84) and without (n = 278) DM had significantly higher DPP4 levels (11.8 ± 3.1 vs. 6.9 ± 3.5 ng/mL, P<0.01) than the nonCAD subjects. The acute coronary syndrome patients (n = 299) had elevated DPP4 levels than those with stable angina patients (n = 83). CAD patients even without DM had increased plasma DPP4 activities as compared with nonCAD subjects (10.9 ± 4.9 vs. 6.4 ± 3.1, ng/L, P< 0.01). A linear regression analysis revealed that overall, the DPP4 levels were positively associated with LCL-C and hs-CRP levels as well as syntax scores. A multiple logistic regression analysis demonstrated that plasma DPP4 activity was independent predictor of CAD (odds ratio, 1.56; 95% CI, 1.19-1.73; P<0.01). Our study shows that increased DPP4 activity levels are associated with the presence of CAD and that the plasma DPP4 level serves as a novel biomarker for CAD even without DM.
Abstract Background The mechanism by which vascular regeneration declines with aging is not fully understood. An interaction between integrin and vascular endothelial growth factor receptor-2 ...(VEGFR-2) plays a substantial role in angiogenesis. Here, we investigated whether aging impairs this interaction in endothelial progenitor cells (EPCs) under hypoxia. Methods and results Aging reduced the blood flow and vessel density in ischemic muscles in mice. Levels of phosphorylated Src (p-Src), p-β3 , and p-VEGFR-2 in acute ischemia were reduced in the muscles of aged mice compared to young mice. The hypoxia-inducible factor (HIF)-1α stabilizer deferoxamine improved the age-related impairment of angiogenesis, but this effect was diminished by LY290004, an inhibitor of phosphatidylinositol 3-kinase. Deferoxamine improved the reduction in chronic ischemia-induced β3 -integrin and VEGFR-2 phosphorylation in the muscles of aged mice; this effect was also diminished by LY290004. In EPCs, we identified the molecular requirements for VEGF-mediated β3 -integrin and VEGFR-2 cross-activation in vitronectin-induced cell adhesion under acute hypoxia. We demonstrated that c-Src controlled the adhesion- and VEGF-induced β3 tyrosine phosphorylation in hypoxia. Aging enhanced the hypoxia-induced EPC apoptosis and impaired several c-Src-related VEGF-induced receptor events, including β3 tyrosine activation, ligand binding, cell adhesion, and tubulogenesis in cultured EPCs of animals and those of humans. Conclusions These data suggest that the aging-related decline in angiogenic action in response to ischemia is mediated by the impairment of cross-activation between β3 and VEGFR-2 in EPCs, which is partially associated with decreased HIF-1α stability.
Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients ...with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.
Background The present study was designed to investigate the effect and relationship of endothelial function and endothelial progenitor cells (EPCs) by green tea consumption in chronic smokers. The ...numbers of circulating EPCs have an inverse correlation with chronic smoking and endothelial dysfunction. Green tea catechin improved endothelial dysfunction in chronic smokers. Method and Results In 20 young healthy smokers, endothelial functions, defined by flow-mediated endothelium dependent vasodilation (FMD) of the brachial artery via ultrasound as well as the number of EPCs isolated from peripheral blood, were determined at baseline and at 2 weeks after green tea consumption (8 g/day). Circulating EPCs were quantified by flow cytometry as CD45lowCD34 + KDR2+ cells and by acyl-low-density lipoprotein and fluorescein isotiocyanate-lectin double positive cells after culture for 7 days. Clinical characteristics and laboratory findings were not significantly different between the baseline and at 2 weeks after green tea intake. EPC levels were inversely correlated with the number of cigarettes smoked. Circulating EPCs by flow cytometry (78.6 ±72.6 vs 156.1±135.8 /ml, p<0.001) and cultured EPCs (118.2±35.7 vs 169.31±58.3/10 field, p<0.001) increased rapidly at 2 weeks after green tea consumption. FMD was significantly improved after 2 weeks (7.2±2.8 vs 9.3±2.4, p<0.001). The FMD correlated with EPC counts (r=0.67, p=0.003) before treatment and after 2 weeks (r=0.60, p=0.013). Conclusions A short-term administration of green tea consumption induces a rapid improvement of EPC levels and FMD. Green tea consumption may be effective to prevent future cardiovascular events in chronic smokers. (Circ J 2006; 70: 1052 -1057)
The favorable effects of the peroxisome proliferator-activated receptor-γ ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the ...bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)–induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-β1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-β1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II–induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II–infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II–induced pathological cardiac remodeling via an adiponectin-dependent mechanism.
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