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Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, which is usually caused by exposure to noxious particles or gases. Hydrogen sulfide (H2S), as an endogenous gasotransmitter, is involved in the pathogenesis of COPD, but its role in COPD is little known. To investigate the role of H2S in COPD, a rat model of COPD was established by cigarette smoking (CS) and intratracheal instillation of lipopolysaccharide (LPS). Rats were randomly divided into 4 groups: control, CS + LPS , CS + LPS + sodium hydrosulfide (NaHS, H2S donor), and CS + LPS + propargylglycine (PPG, inhibitor of cystathionine-γ-lyase, and CTH). Lung function in vivo, histology analysis of lung sections, malondialdehyde (MDA) concentration, CTH protein, total superoxide dismutase (T-SOD), and catalase (CAT) activity in lung tissues were assessed. Gene expression profiling of lung was assessed by microarray analysis. The results showed that rats in the CS + LPS group had lower body weight and lung function but higher lung pathological scores, MDA concentration, CTH protein, T-SOD, and CAT activity compared with the control. Compared with CS + LPS group, NaHS treatment decreased lung pathological scores and MDA concentration, while PPG treatment decreased body weight of rats and T-SOD activity, and no significant differences were detected in pathological scores by PPG treatment. Microarray analysis identified multiple differentially expressed genes, and some genes regulated by H2S were involved in oxidative stress, apoptosis, and inflammation pathways. It indicates that H2S may play a protective role in COPD via antioxidative stress and antiapoptosis pathway.

Vascular aging is a specific type of organic aging that plays a central role in the morbidity and mortality of cardiovascular and cerebrovascular diseases among the elderly. It is essential to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes. Endogenous vasoactive peptides are compounds formed by a group of amino acids connected by peptide chains that exert regulatory roles in intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that a variety of vasoactive peptides play important roles in the occurrence and development of vascular aging and related diseases such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, and stroke. This review will summarize the cumulative roles and mechanisms of several important endogenous vasoactive peptides in vascular aging and vascular aging-related diseases. In addition, we also aim to explore the promising diagnostic function as biomarkers and the potential therapeutic application of endogenous vasoactive peptides in vascular aging-related diseases.

The change in plasma apelin level in heart failure (HF) patients is controversial. We investigated the change in plasma apelin level in HF patients versus control and non-HF patients. The plasma level of apelin was measured by ELISA and plasma level of B-type natriuretic peptide (BNP) by fluorescence immunoassay. We included 101 patients with HF, 32 patients without HF and 20 controls. The three groups did not differ in general and clinical characteristics. Plasma levels of apelin and BNP were both higher in HF patients than non-HF patients and controls. Plasma levels of apelin and BNP were not correlated. Plasma level of BNP was increased with increasing New York Heart Association grade and apelin level was decreased. Apelin level was lower in HF patients with NYHA grade IV than in controls and non-HF patients. Apelin level had 75% diagnostic value for HF, and BNP level had 96.8% diagnostic value. At a cutoff of 6.44 ng/mL apelin level, sensitivity was 69.3%, and specificity 97.1%. However, the diagnostic of apelin for NYHA II patients was higher than that of BNP (99.6% vs. 96.1%). These results suggested that apelin might be particularly useful in association with BNP in mild HF patients.

The ternary complex photocatalysts of BiOIO3/g-C3N4/MoS2 by solvent-exfoliation method was synthesized for the first time. In the typical procedure, the BiOIO3/g-C3N4 was obtained via hydrothermal synthesis technique, and then the BiOIO3/g-C3N4/MoS2 photocatalysts were prepared via ultrasonic solvent-exfoliation method from bulk commercial MoS2 in the alcohol solution. The samples of BiOIO3/g-C3N4/MoS2 were analyzed by PL, XRD and other characterization analysis methods. The photocatalytic activity of the as-prepared samples was investigated by removing gas phase mercury irradiation under visible light. The as-prepared BCM-0.3 exhibits excellent photocatalytic performance, being with the highest efficiency of 70.58%. Owing to the electronic channels of field-effect, an internal electric field was formed through the corresponding band-gap engineering, improving photocatalytic reaction. Besides, the excellent activity of the ternary photocatalysts BiOIO3/g-C3N4/MoS2 is attributed to heterostructure between BiOIO3/g-C3N4 and MoS2, which enlarges spectral response and improved separation efficiency of charge carriers, and MoS2-composing, which provides more active sites for catalytic oxidation. In addition, the as-prepared samples with excellent photocatalytic performance also offer a perspective insight into the hydrogen evolution, CO2 conversion and degradation of organic pollutants.

Background To improve the poor prognosis of congestive heart failure (CHF), early and accurate diagnosis is necessary. Relaxin is an endogenous cardiovascular peptide, and its plasma level is usually increased in patients with CHF. In this pilot study, we aimed to determine the diagnostic value of relaxin and B-type natriuretic peptide (BNP) in patients with and without CHF. Materials and Methods The plasma level of relaxin was measured by enzyme-linked immunosorbent assay and plasma level of BNP by fluorescence immunoassay. The area under the receiver operating characteristic curve was used to assess the diagnostic value of relaxin and BNP. Results We included 81 patients with decompenstated CHF and 36 controls. Plasma levels of relaxin and BNP were both higher in CHF patients than in controls. The correlation between plasma levels of relaxin and BNP and between relaxin or BNP and cardiac function was nonlinear. Relaxin had medium diagnostic value, and BNP had higher value for cardiac function and CHF. At a cutoff of 39.76 pg/mL relaxin, sensitivity was 82.7%, specificity 55.6%, sum of the highest positive predictive value 80.5% and negative predictive value 58.8%. Although the diagnostic value was not better for relaxin than BNP, their combined assessment improved the sensitivity and specificity of diagnosis for CHF as compared with BNP alone. Conclusions Combined assessment of relaxin and BNP may improve the diagnosis of decompensated CHF, which may have potential application in the clinic.

The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, in vitro assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. In vivo, administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.

// Li Liu 1 , Nana Tian 1 , Chengyu Zhou 2 , Xinqi Lin 1 , Weibiao Lv 3 , Zhifeng Lin 1 , Zibo Lin 1 , Yongfen Qi 1 , Yi Yang 1 , Sidong Chen 1 , Xinfa Yu 2 , Yanhui Gao 1 1 Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China 2 Department of Oncology, Shunde First People’s Hospital, Foshan, China 3 Department of Clinical Laboratory, Shunde First People’s Hospital, Foshan, China Correspondence to: Yanhui Gao, email: gao_yanhui@163.com Xinfa Yu, email: yuxfa@126.com Keywords: ARID1B, genetic variant, functional annotation, gene-environment interaction, hepatocellular carcinoma Received: September 06, 2016 Accepted: February 27, 2017 Published: March 10, 2017 ABSTRACT The tumor suppressor role of AT-rich interactive domain containing protein 1B ( ARID1B ) has drawn much attention in area of cancer etiology. However, it had remained unknown whether or not genetic variants of ARID1B involved in development of hepatocellular carcinoma (HCC). In this study, three putatively functional variants in ARID1B (rs73013281C>T, rs167007A>G, and rs9397984C>T) were selected using bioinformatics tools, and a case-control study of 611 cases and 614 controls was conducted to investigate genetic associations with HCC risk in a Southern Chinese population. Two-dimensional gene-environment interactions were also explored using both multiplicative and additive scales. A dominant effect of the rs73013281 was found for HCC risk, with an adjusted odds ratio (OR) of 1.70 [95% confidence interval (CI) = 1.03−2.80] for the CT/TT genotypes compared to the CC genotype. In stratified analysis, the detrimental effect of the T allele on elevated HCC risk was attenuated by physical activity, with an adjusted OR of 2.75 (95% CI = 1.39−5.41) among inactive individuals against that of 0.89 (95% CI = 0.42−1.91) in those who exercised regularly. Expectably, the rs73013281 showed both multiplicative and additive interactions with physical activity ( P = 0.037 and 0.006, respectively). In conclusion, these results highlighted the significant genetic contribution of the ARID1B variant, rs73013281, to susceptibility for HCC, especially in interaction with physical activity.

Pheochromocytomas and left ventricular noncompaction (LVNC) are both rare diseases. In this patient, the long duration of the catecholamine-secreted pheochromocytoma caused myocardial ischemia, pressure overload, and hypertrophy, resulting in the onset of heart failure (HF). The LVNC might be associated with the acute attack of HF induced by the pheochromocytoma. This is the first case reporting LVNC in combination with HF secondary to pheochromocytoma.

Sepsis is a disease that occurs as a result of systemic inflammatory response syndrome (SIRS) in response to an infection, contributing to multiple organ dysfunction and a high mortality rate. Interleukin-lβ (IL-1β) is a cytokine that plays critical roles in inflammation and cardiac dysfunction during severe sepsis. Intermedin

Sustained inflammation is associated with pulmonary vascular remodeling and arterial hypertension (PAH). Serum-glucocorticoid regulated kinase 1 (SGK1) has been shown to participate in vascular remodeling, but its role in inflammation-associated PAH remains unknown. In this study, the importance of SGK1 expression and activation was investigated on monocrotaline (MCT)-induced PAH, an inflammation-associated experimental model of PAH used in mice and rats. The expression of SGK1 in the lungs of rats with MCT-induced PAH was significantly increased. Furthermore, SGK1 knockout mice were resistant to MCT-induced PAH and showed less elevation of right ventricular systolic pressure and right ventricular hypertrophy and showed reduced pulmonary vascular remodeling in response to MCT injection. Administering the SGK1 inhibitor, EMD638683, to rats also prevented the development of MCT-induced PAH. The expression of SGK1 was shown to take place primarily in alveolar macrophages. EMD638683 treatment suppressed macrophage infiltration and inhibited the proliferation of pulmonary arterial smooth muscle cells (PASMCs) in the lungs of rats with MCT-induced PAH. Co-culture of bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice promoted proliferation of PASMC in vitro, whereas BMDMs from either SGK1 knockout mice or WT mice with EMD638683 treatment failed to induce this response. Collectively, the present results demonstrated that SGK1 is important to the regulation of macrophage activation that contributes to the development of PAH; thus, SGK1 may be a potential therapeutic target for the treatment of PAH.

Background: The epithelial-mesenchymal transition (EMT) induced by growth factors or cytokines, particularly transforming growth factor-β (TGF-β1), plays an important role in kidney tubulointerstitial injury. However, signaling pathways mediating TGF-β1-induced EMT are not precisely known. In this study, we examined the role of Akt2 on EMT. Methods: HK-2 cells were exposed to 10 ng/ml TGF-β1 to establish a model of EMT. The expression of proteins were detected by western blot assay and Immunofluorescence. The levels of genes were tested by RT-PCR. Results: We found that treatment of HK-2 cells, a human proximal tubular cell line, with 10 ng/ml TGF-β1 resulted in activation of phosphatidylinositol 3-kinase (PI3K)/Akt2 signaling as evidenced by increased p-PI3K, Akt2 and p-Akt (Ser 473) expression. Importantly, TGF-β1 treatment decreased zona occludins 1 (ZO-1) and E-cadherin (epithelial markers) expression, increased fibronectin and vimentin (mesenchymal makers) expression, which were prevented by Ly294002 (the inhibitor of PI3K) or small interfering RNA (siAkt2), suggesting that Akt2 mediated TGF-β1-induced EMT. Meanwhile, RNA and protein levels of Snail1, the key inducer of EMT, were significantly elevated in TGF-β1-treated HK-2 cells. TGF-β1 also induced inactivation of glycogen synthase kinase-3β (GSK3β), an endogenous inhibitor of Snail. Knockdown of Akt2 using siRNAs or the PI3K inhibitor Ly294002 inhibited TGF-β1-induced phosphorylation of GSK3β and expression of Snail1. Conclusion: These findings revealed that knockdown of Akt2 antagonized TGF-β1-induced EMT by inhibiting GSK3β/Snail signaling pathway.

Aims Cathepsin S (Cat S) is a potent lysosomal protease that is secreted into the extracellular space and has been implicated in elastin and collagen degradation in diseases such as atherosclerosis. Elastin degradation plays an important role in vascular remodelling. However, the mechanism by which Cat regulates this process and its contribution to vein graft remodelling remains unclear. Methods and results Using a murine vein graft model, we examined the expression pattern of Cat family members. Expression of cathepsin genes was induced in vein grafts, with that of Cat S being the highest. Elevated Cat S expression was confirmed in both mouse and human vein grafts. To explore the role of Cat S, vein grafts were created between wild-type (WT) littermates and Cat S knockout (Cat S KO) mice. Knockout of Cat S in the recipients (veinCatS-KO-arteryCatS-KO or veinWT-arteryCatS-KO) significantly inhibited neointima formation and reduced the accumulation of macrophages and proliferation of smooth muscle cells in vein grafts. Knockout of Cat S preserved the elastic fibre integrity of vein grafts and inhibited the migration of macrophages across the elastin fibres. Conclusion These results demonstrated that Cat S contributes to macrophage migration via degradation of elastic fibre integrity to facilitate neointima formation of vein grafts, which might provide a novel therapeutic target for preserving vein graft patency.

The regulator of G-protein signaling 2 (RGS2) has been shown to be crucial in the regulation of vascular tone and blood pressure. The vascular activities of adrenomedullin (ADM) and adrenotension (ADT), two natural peptides, are dependent upon the modulation of RGS2 expression. However, the effects and pathways involved in their modulation remain unknown. This study aimed to observe the changes of RGS2 expression in response to ADM and ADT in cultured vascular smooth muscle cells and to clarify the potential signaling pathways in vitro. In the present study, vascular smooth muscle cells (VSMCs) were cultured with ADM and ADT of various concentrations for different time periods, and the gene expression of RGS2 was analyzed by PCR. ADM significantly increased the gene expression at 0.5 h to ~35-fold of that at baseline, whereas ADT marginally increased the expression after 1-2 h. SQ22,536 and chelerythrine were used to block the protein kinase A (PKA) and PKC pathways activated by incubation with ADM. The gene expression of RGS2 was reduced by SQ22,536 only. Furthermore, when SQ22,536 and chelerythrine were added to the cells incubated with ADT, the gene expression was markedly reduced by both SQ22,536 and chelerythrine. In conclusion, ADM immediately showed a marked increase in the gene expression of RGS2 in cultured VSMCs via a cAMP-dependent pathway and ADT gradu- ally showed a marginal increase in the gene expression via a cAMP-dependent pathway and a PKC pathway.

Our previous work reported that endoplasmic reticulum stress (ERS)-mediated apoptosis was activated during vascular calcification (VC). Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis. However, whether ATF4 is involved in ERS-mediated apoptosis contributing to VC remains unclear. In the present study, in vivo VC was induced in rats by administering vitamin D3 plus nicotine. Vascular smooth muscle cell (VSMC) calcification in vitro was induced by incubation in calcifying media containing β-glycerophosphate and CaCl2. ERS inhibitors taurine or 4-phenylbutyric acid attenuated ERS and VSMC apoptosis in calcified rat arteries, reduced calcification and retarded the VSMC contractile phenotype transforming into an osteoblast-like phenotype in vivo. Inhibition of ERS retarded the VSMC phenotypic transition into an osteoblast-like cell phenotype and reduced VSMC calcification and apoptosis in vitro. Interestingly, ATF4 was activated in calcified aortas and calcified VSMCs in vitro. ATF4 knockdown attenuated ERS-induced apoptosis in calcified VSMCs. ATF4 deficiency blocked VSMC calcification and negatively regulated the osteoblast phenotypic transition of VSMCs in vitro. Our results demonstrate that ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to VC.

Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-β-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12-/- mice. SMCs from P2ry12-/- mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.

Intermedin (IMD), an autocrine/paracrine biologically active peptide, plays a critical role in maintaining vascular homeostasis. Recent research has shown that high plasma levels of IMD are associated with poor outcomes for patients with ST-segment elevation acute myocardial infarction. However, the prognostic utility of IMD levels in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) has not yet been investigated. We hypothesized that the level of plasma IMD would have prognostic value in patients with NSTE-ACS. Plasma IMD was determined by radioimmunoassay in 132 NSTE-ACS patients on admission to hospital and 132 sex- and age-matched healthy-control subjects. Major adverse cardiovascular events (MACEs), including death, heart failure, hospitalization, and acute myocardial infarction, were noted during follow-up. In total, 23 patients suffered MACEs during the follow-up period (mean 227 ± 118 days, range 2–421 days). Median IMD levels were higher in NSTE-ACS patients than control [320.0 (250.9/384.6) vs. 227.2 (179.7/286.9) pg/mL, P

To explore the effects of hydrogen sulfide on nicotine-induced bronchial epithelial cell endoplasmic reticulum (ER) stress and apoptosis.Nicotine was used to establish the apoptotic model in human bronchial epithelial cell line (16HBE) for mimicing the effect of cigarette smoke on apoptosis. The 16HBE cells were grouped by the concentration gradients of 0 (control), 5, 10, 20, 40, 80 µmol/L nicotine dosing. All groups were treated for 72 h. And 16HBE cells were grouped by the time gradients of 0 (control), 24, 48, 72 h of nicotine dosing. For control group, the nicotine concentration was 40 µmol/L. Then the protein expression level of CCAAT/enhancer binding protein homologous protein (CHOP) was measured by Western blot to define the effect of various concentrations of nicotine and different dosing periods of nicotine on the protein expression level of CHOP. For observing the role of hydrogen sulfide in ER stress-mediated apoptosis, 16HBE cells were divided into 6 groups of control, 40 µmol/L nicotine, 100 µmol/L sodium hydrosulfide (NaHS) + 40 µmol/L nicotine, 200 µmol/L NaHS + 40 µmol/L nicotine, 400 µmol/L NaHS + 40 µmol/L nicotine and 10 mmol/L taurine + 40 µmol/L nicotine. NaHS or taurine was pretreated for 30 min and then nicotine dosed for 72 h. The protein expression levels of GRP78 and ER stress-mediated apoptosis markers, such as cleaved caspase-12 and CHOP, were measured by Western blot. And chromatin dye Hoechst 33258 was used to detect the morphological changes of apoptotic 16HBE cells and apoptotic index calculated.Nicotine could concentration and time-dependently improve the expression of CHOP in 16HBE cells. The ratio of CHOP to average absorbance of glyceraldehyde phosphate dehydrogenase (GAPDH) was significantly higher in 40 µmol/L nicotine group than that in control group (1.04 ± 0.32 vs 0.30 ± 0.17, P0.05). The ratio of GRP78 to average absorbance of β-actin (0.59 ± 0.19 vs 1.00 ± 0.08), cleaved caspase-12 to average absorbance of procaspase-12 (0.06 (0.01, 6.06) vs 20.30(12.79, 23.78)) and CHOP to average absorbance of β-actin (0.18 ± 0.10 vs 0.53 ± 0.09) in 200 µmol/L NaHS + 40 µmol/L nicotine group were all significantly lower than those in 40 µmol/L nicotine group (all P0.05). The apoptotic index in 200 µmol/L NaHS + 40 µmol/L nicotine group (3.04 ± 1.83 vs 16.60 ± 3.32) and apoptotic index in 10 mmol/L taurine + 40 µmol/L nicotine group (4.08 ± 2.04 vs 16.60 ± 3.32) were significantly lower than those in 40 µmol/L nicotine group (all P0.01).NaHS exerts its protection against nicotine-induced bronchial epithelial cell apoptosis through suppressing ER stress. And the underlying mechanism may be through a down-regulation of ER stress-mediated apoptosis markers of cleaved caspase-12 and CHOP.

To explore the role of cortistatin (CST) in rats with chronic obstructive pulmonary disease (COPD).A total of 16 healthy male Sprague-Dawley rats were randomly divided into control and COPD model groups (n=8 each). The COPD model group received an inhalation of passive smoking while the control group was treated normally. After 4 months, pulmonary function was measured. The differential cell counts of bronchoalveolar lavage fluid (BALF) were detected. Morphology and pathology of lungs were studied via hematoxylin and eosin staining. The levels of CST in lung tissue, serum and BALF were detected by radioimmunoassay.Compared with the control group, the COPD group had obviously higher airway resistance and neutrophil ratio in BALF [(0.584 ± 0.021) vs (0.653 ± 0.062) mmHg·ml⁻¹·s⁻¹, 1.49% vs 0.41%, both P0.05]. And there were significantly serious inflammation and emphysema in lung tissues. Moreover, the levels of CST increased in serum, BALF and lung tissues [(526 ± 76) vs (453 ± 41)pg/ml, (819 ± 100) vs (619 ± 101)pg/ml, (41 ± 10) vs (20 ± 7)pg/mg, all P0.05] respectively as compared with the controls.An elevated level of CST may compensate to exert anti-inflammation effects in COPD rats.

Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown. Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl 2 to the abdominal aorta. COMP protein level was markedly reduced in both calcified VSMCs and arteries. COMP deficiency remarkably exacerbated VSMC calcification, whereas ectopic expression of COMP greatly reduced calcification. Furthermore, COMP knockdown facilitated osteogenic markers expression by VSMCs even in the absence of calcifying media. By contrast, COMP overexpression significantly inhibited high phosphate– or high calcium–induced VSMC osteochondrogenic transition. Induction of osteogenic marker expression by COMP silencing was reversed by a soluble form of bone morphogenetic protein (BMP)-2 receptor IA, which suggests a BMP-2–dependent mechanism. Our data revealed that COMP bound directly to BMP-2 through the C terminus, inhibited BMP-2 receptor binding, and blocked BMP-2 osteogenic signaling, indicating COMP inhibits osteochondrogenic transition of VSMCs at least partially through inhibiting BMP-2. Conclusions: Our data strongly suggest that COMP is a novel inhibitor of vascular calcification. The imbalance between the effects of COMP and BMP-2 may provide new insights into the pathophysiology of vascular calcification.

TZDs (thiazolidinediones) are prescribed as anti-Type II diabetes drugs, but little is known regarding whether TZDs regulate the expression of sPLA2 (secretory phospholipase A2) in macrophages. We have investigated the effects of pioglitazone on LPS (lipopolysaccharide)-induced production of TNF-alpha (tumour necrosis factor alpha), sPLA2-V and -X (groups V and X sPLA2) in RAW 264.7 macrophages. TNF-alpha, sPLA2-V and -X mRNA and protein expression were determined by RT-PCR (reverse transcriptase-PCR) and Western blot analysis, respectively. The activity of NF-kappaB (nuclear factor kappaB) was determined by Western blot and confocal microscopy. LPS induced TNF-alpha, sPLA2-V and sPLA2-X mRNA and protein expression. Pretreatment with 10 mumol/l pioglitazone significantly suppressed LPS-induced TNF-alpha, sPLA2-V and sPLA2-X mRNA and protein expression. LPS induced NF-kappaB expression and translocation in the nucleus, but the inductive effects were inhibited by pioglitazone. Our findings indicate that pioglitazone inhibits production of inflammatory factors induced by LPS in murine macrophage cells by inactivating NF-kappaB. Pioglitazone appears to play an anti-inflammatory role in the atherosclerotic process.

Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. We here report that treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor (TNF) α substantially increased the expression of MCP-induced protein 1 (MCPIP1). Overexpression of MCPIP1 protected ECs against TNFα-induced endothelial activation, as characterized by the attenuation in the expression of the adhesion molecule VCAM-1 and monocyte adherence to ECs. Conversely, small interfering RNA-mediated knock down of MCPIP1 increased the expression of VCAM-1 and monocytic adherence to ECs. These studies identified MCPIP1 as a feedback control of cytokines-induced endothelial inflammation.

Clinical studies have suggested that metformin, a widely used antidiabetic agent, exerts a direct cardioprotective effect on cardiovascular disease in addition to its blood glucose-lowering activity. This study was designed to identify the role of metformin in rats with isoproterenol (ISO)-induced myocardial injury and to investigate its underlying mechanism. A rat model of myocardial ischemic injury was established by the subcutaneous injection of a high dose of ISO, a beta-adrenergic agonist. The results showed that pretreatment of metformin significantly reduced rat mortality induced by ISO, attenuated the increased plasma lactate dehydrogenase activity and myocardium malondialdehyde level, alleviated the hemodynamic disturbance, inhibited the upregulated gene expression of myocardial probrain natriuretic peptide and alleviated the myocardial morphological injury and apoptosis induced by ISO. Furthermore, western blot analysis showed that metformin suppressed the overexpression of the endoplasmic reticulum stress (ERS) markers cleaved caspase-12 and CEBP-homologous protein induced by ISO and increased the phosphorylation of AMP-activated protein kinase (AMPK). In conclusion, these data suggest that metformin might protect the myocardium against acute ischemic injury in rats at least partially by activating AMPK and alleviating aberrant ERS. These findings might provide further experimental evidence for treating patients at risk of ischemic heart disease with metformin.

Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.

Interleukin-6 (IL-6) is an important cytokine participating in multiple biologic activities in immune regulation and inflammation. IL-6 has been associated with cardiovascular remodeling. However, the mechanism of IL-6 in hypertensive cardiac fibrosis is still unclear. Angiotensin II (Ang II) infusion in mice increased IL-6 expression in the heart. IL-6 knockout (IL-6-/-) reduced Ang II-induced cardiac fibrosis: 1) Masson trichrome staining showed that Ang II infusion significantly increased fibrotic areas of the wild-type mouse heart, which was greatly suppressed in IL-6-/- mice and 2) immunohistochemistry staining showed decreased expression of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and collagen I in IL-6-/- mouse heart. The baseline mRNA expression of IL-6 in cardiac fibroblasts was low and was absent in cardiomyocytes or macrophages; however, co-culture of cardiac fibroblasts with macrophages significantly increased IL-6 production and expression of α-SMA and collagen I in fibroblasts. Moreover, TGF-β1 expression and phosphorylation of TGF-β downstream signal Smad3 was stimulated by co-culture of macrophages with cardiac fibroblasts, while IL-6 neutralizing antibody decreased TGF-β1 expression and Smad3 phosphorylation in co-culture of macrophage and fibroblast. Taken together, our results indicate that macrophages stimulate cardiac fibroblasts to produce IL-6, which leads to TGF-β1 production and Smad3 phosphorylation in cardiac fibroblasts and thus stimulates cardiac fibrosis.

Modification and functionalization of substrates can lead to the presence at materials surfaces of molecular nanostructures. Their 2D packing and chemical functionalities may impart to surfaces particular properties that can be very different from the pristine ones. Modification is a very general term concerning every kind of treatment leading to change the physical morphology or surface chemistry of a given material in order to obtain tailored properties with dependence on the material application field. Functionalization is mainly related to the introduction at a surface of chemical groups with a variable surface density which are requested to subsequently react with other species. When a process or a group of processes are applied to the surface of an inorganic or organicmaterial, affecting both topography/morphology and surface chemistry at the micro- and/or nanoscale level, the material surface results physically and chemically patterned. In the following the main modification, functionalization, and patterning surface techniques will be described according to process methods, substrate chemistry, and nanotechnological application fields