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Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles. Studies in experimental disease models and on cathepsin-selective inhibitors, as well as plasma and tissue biomarker data from animal models and humans, have verified the participation of cysteinyl cathepsins in the pathogenesis of many cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, cardiomyopathy, abdominal aortic aneurysms, and hypertension. Clinical trials of cathepsin inhibitors in chronic inflammatory diseases suggest the utility of these inhibitors for the treatment of cardiovascular diseases and associated complications. Moreover, development of cell transfer technologies that enable ex vivo cell treatment with cathepsin inhibitors might limit the unwanted systemic effects of cathepsin inhibition and provide new avenues for targeting cysteinyl cathepsins. In this Review, we summarize the available evidence implicating cysteinyl cathepsins in the pathogenesis of cardiovascular diseases, discuss their potential as biomarkers of disease progression, and explore the potential of cathepsin inhibitors for the treatment of cardiovascular diseases.

Background A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. Methods We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (N case  = 12,550, N control  = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) ( N  = 458,969), high blood pressure (HBP) (N case  = 144,793, N control  = 313,761), coronary artery disease (CAD)(N case  = 60,801, N control  = 123,504), and stroke (N case  = 40,585, N control  = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. Results RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P  = 0.008). Conclusion In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.

The pH in atherosclerotic lesions varies between individuals. IgE activates macrophage Na + -H + exchanger (Nhe1) and induces extracellular acidification and cell apoptosis. Here, we show that the pH-sensitive pHrodo probe localizes the acidic regions in atherosclerotic lesions to macrophages, IgE, and cell apoptosis. In Apoe –/– mice, Nhe1-deficiency or anti-IgE antibody reduces atherosclerosis and blocks lesion acidification. Reduced atherosclerosis in Apoe –/– mice receiving bone marrow from Nhe1- or IgE receptor FcεR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FcεR1 in IgE-activated macrophages, and Nhe1-FcεR1 colocalization in atherosclerotic lesion macrophages support a role of IgE-mediated macrophage Nhe1 activation in atherosclerosis. Intravenous administration of a near-infrared fluorescent pH-sensitive probe LS662, followed by coregistered fluorescent molecular tomography-computed tomography imaging, identifies acidic regions in atherosclerotic lesions in live mice, ushering a non-invasive and radiation-free imaging approach to monitor atherosclerotic lesions in live subjects. Na+-H+ exchanger 1 (Nhe1) regulates extracellular pH by extruding protons in exchange for extracellular Na+ . Here, Liu et al. show that Nhe1 promotes the development and acidification of atherosclerotic lesions and that pH-sensitive probes can be used to monitor plaque growth and acidification.

White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r −/− Ncc −/− mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r −/− mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues. Interleukin-18 (IL18) has a pivotal role in interferon signalling and T cell development, but increasingly recognized as an adipokine that regulates energy metabolism in fat tissue. Authors here dissect the function of IL18 signalling in the adipose compartment by targeted genomic deletion of its two receptors individually and in combination in brown and white adipose tissues.

Toll-like receptor 7 (TLR7) mediates autoantigen and viral RNA-induced cytokine production. Increased TLR7 expression in human atherosclerotic lesions suggests its involvement in atherogenesis. Here we demonstrated TLR7 expression in macrophages, smooth muscle cells (SMCs), and endothelial cells from mouse atherosclerotic lesions. To test a direct participation of TLR7 in atherosclerosis, we crossbred TLR7-deficient ( Tlr7 −/− ) mice with apolipoprotein E-deficient ( Apoe −/− ) mice and produced Apoe −/− Tlr7 −/− and Apoe −/− Tlr7 +/+ littermates, followed by feeding them an atherogenic diet to produce atherosclerosis. Compared to Apoe −/− Tlr7 +/+ mice, Apoe −/− Tlr7 −/− mice showed reduced aortic arch and sinus lesion areas. Reduced atherosclerosis in Apoe −/− Tlr7 −/− mice did not affect lesion macrophage-positive area and CD4 + T-cell number per lesion area, but reduced lesion expression of inflammatory markers major histocompatibility complex-class II and IL6, lesion matrix-degrading proteases cathepsin S and matrix metalloproteinase-9, and systemic serum amyloid A levels. TLR7 deficiency also reduced aortic arch SMC loss and lesion intima and media cell apoptosis. However, TLR7 deficiency did not affect aortic wall elastin fragmentation and collagen contents, or plasma lipoproteins. Therefore, TLR7 contributes to atherogenesis in Apoe −/− mice by regulating lesion and systemic inflammation. A TLR7 antagonist may mitigate atherosclerosis.

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response.

Background Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression. Methods and results Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P =0.007), MMP-22 (OR=1.213, P =0.040), and MMP-29 (OR=1.198, P =0.033) were independent risk factors of CHD. Pearson’s correlation test showed that IL18 (coefficient ( r )=0.214, P =0.045; r =0.246, P =0.031) and MMP-22 ( r =0.273, P =0.006; r =0.286, P =0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson’s correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) ( r =0.167, P =0.023), and MMP-29 levels correlated negatively with triglyceride ( r =−0.169, P =0.018). Spearman’s correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 ( r =0.845, P <0.001) and MMP-29 ( r =0.548, P <0.001). Conclusions Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29 levels in these patients.

The purpose of this study was to investigate the levels of interleukin-33 (IL-33) and interleukin-6 (IL-6) in patients with acute coronary syndrome or stable angina. Serum IL-33 and IL-6 were measured with Enzyme Linked Immuosorbent Assay (ELISA) in patients with acute coronary syndrome (ACS, n=40), and stable angina pectoris (SAP, n=43). IL-33 and IL-6 were also determined in 30 healthy subjects (control group). The serum level of IL-33 in the ACS group (78.60±44.84 ng/L) was lower than in the SAP (102.58±37.21 ng/L, P<0.01) or control groups (130.24±10.17 ng/L, P<0.01). The serum level of IL-6 in the ACS group (39.90±12.64 ng/L) was higher than in the SAP (18.68±11.89 ng/L, P<0.05) or control groups (6.28±17.72 ng/L, P<0.05). There were no differences in serum levels of IL-33 and IL-6 among the single-, double- and triple-vessel lesion groups. IL-33 and IL-6 levels were negatively correlated with each other in the ACS (r=-0.871, P<0.01) and SAP groups (r=-0.788, P<0.01). The serum level of IL-33 was lower in patients with ACS or SAP and was negatively correlated with the serum level of IL-6. Thus, IL-33 and IL-6 may be used as biomarkers for evaluating inflammatory response and severity of coronary heart disease in patients with ACS or SAP.

Modern solid-propellant rocket motors (SRM) are laden with aluminum powder to increase the specific impulse. In SRM chamber, on the one hand, aluminum droplets evaporate and burn to form alumina smoke, on the other hand, the alumina smoke agglomerates to droplets as droplets collide with each other. The agglomeration model is employed to simulate the burning droplets. And breakup model also used. To avoid complex reaction theory, the article solves the mass, momentum and heat equations of disperse and continuity phases to simulate the chemic reaction. Results showed that burning efficiency and agglomeration of droplet varied by different initial diameters, and the temperature as well as smoke concentration also changed, especially in nozzle inlet.

Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms 1 , 2 . Interruption of IL18 action reduces atherosclerosis in mice 3 , 4 . Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E–deficient ( Apoe −/− ) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney 5 . NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe −/− mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe −/− mice or from Apoe −/− mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe −/− mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.