Myocardin‐related transcription factor (MRTF)‐A is a Rho signalling‐responsive co‐activator of serum response factor (SRF). Here, we show that induction of MRTF‐A expression is key to pathological vascular remodelling. MRTF‐A expression was significantly higher in the wire‐injured femoral arteries of wild‐type mice and in the atherosclerotic aortic tissues of ApoE−/− mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire‐injured femoral arteries in MRTF‐A knockout (Mkl1−/−) mice and atherosclerotic lesions in Mkl1−/−; ApoE−/− mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP‐9) and integrin β1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1−/− mice than in wild‐type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF‐A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF‐A expression in dedifferentiated VSMCs was the downregulation of microRNA‐1. Moreover, the MRTF‐A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF‐A could thus be a novel therapeutic target for the treatment of vascular diseases.

BackgroundThe efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization‐activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.Methods and ResultsWe examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF‐Tg) expressing a cardiac‐specific dominant‐negative form of neuron‐restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF‐Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF‐Tg ventricular myocytes. Moreover, cardiac‐specific overexpression of HCN2 in mice (HCN2‐Tg) made hearts highly susceptible to arrhythmias induced by chronic β‐adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2‐Tg mice were highly susceptible to β‐adrenergic stimulation‐induced abnormal automaticity, which was inhibited by ivabradine.ConclusionsHCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac‐specific overexpression of HCN2 channels increases arrhythmogenicity of β‐adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

During coevolution with the host, HIV-1 developed the ability to hijack the cellular ubiquitin/proteasome degradation pathway to counteract the antiviral activity of APOBEC3G (A3G), a host cytidine deaminase that can block HIV-1 replication. Abrogation of A3G function involves the HIV-1 Vif protein, which binds A3G and serves as an adapter molecule to recruit A3G to a Cullin5-based E3 ubiquitin ligase complex. Structure-guided mutagenesis of A3G focused on the 14 most surface-exposed Lys residues allowed us to identify four Lys residues (Lys-297, 301, 303, and 334) that are required for Vif-mediated A3G ubiquitination and degradation.

Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100–1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy.

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Background-Tumour necrosis factor (TNF) is a predominant cytokine produced in the gastric mucosa of patients with Helicobacter pylori infection. TNF induces apoptosis in a variety of cells. The soluble TNF receptors (sTNF-Rs) can be divided into sTNF-RI and sTNF-RII, both of which inhibit TNF activity. However, their precise mechanisms remain unclear. Aim-To investigate the role of sTNF-Rs in H pylori infection. Methods-In 40 patients, production of TNF and sTNF-Rs in gastric mucosa was measured using biopsy specimens. In addition, in gastric epithelial cells, sTNF-R release in response to TNF and the protective eVect of sTNF-Rs against the cytotoxic and apoptotic activities of TNF were examined. Results-TNF and sTNF-R expression was significantly higher in H pylori positive than H pylori negative patients. TNF dose-dependently induced sTNF-RI release from gastric epithelial cells. sTNF-RII was also released from the cells. TNF decreased cell viability, but the eVect was very small. A combination of antisTNF-RI and anti-sTNF-RII monoclonal antibodies significantly increased TNF induced cytotoxicity and apoptosis of gastric epithelial cells. Conclusions-These results show that sTNF-Rs are actively produced in H pylori infected gastric mucosa. sTNF-Rs appear to protect gastric epithelial cells from TNF induced apoptosis in H pylori infection. (Gut 1999;45:24-31)

YBa2Cu3O7-x (YBCO) films prepared by a metalorganic deposition method using trifluoroacetats (TFA-MOD method) with spin coating have excellent properties: a critical current density (Jc) of over MA cm-2 (77 K, 0 T) and a critical temperature of over 92 K. However, films prepared by spin coating shrink at lower spinning rates or have striation at higher spinning rates. Both shrunk films and films with striation have low Jc. Moreover, even if striation is not observed by scanning electron microscopy scale observation, a structure containing pores was confirmed by transmission electron microscopy. Such pores are considered to result in a low Jc of the films. To avoid such problems we adopted dip coating as the coating process in the TFA-MOD method. The dipped YBCO films have excellent Jc compared to the spun films. A typical dipped YBCO film of 0.25 µm in thickness on LaAlO3 single-crystalline substrate has a transport Jc of 5.3 MA cm-2 (77 K, 0 T).

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