Glycoprotein 130 (gp130), a common receptor of IL-6 family cytokines, plays critical roles in cardiac functions. Here, we demonstrate that the stimulation of gp130 with leukemia inhibitory factor ...(LIF) promoted cell adhesion in a cadherin-dependent manner in cultured cardiomyocytes. Wnt5a was upregulated by the stimulation of gp130 with IL-6 family cytokines, accompanied by N-cadherin protein upregulation. Wnt5a was not induced by LIF in cardiomyocytes expressing dominant-negative STAT3. Ablation of Wnt5a by antisense cDNA inhibited LIF-induced cell adhesion. Collectively, signals through gp130 upregulate Wnt5a through STAT3, promoting the N-cadherin-mediated cell adhesion.
STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after ...myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 ± 6.7% in iCKO mice and 40.8 ± 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 ± 4.1% in iCKO mice and 29.1 ± 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI.
Varenicline has been reported to achieve high rates of smoking cessation. It remains undetermined whether varenicline therapy improves vascular function in smokers.
Consecutive Seventy-two smokers ...(age 57 ± 12 years) who succeeded in complete smoking cessation and 46 normal healthy volunteers (age 24 ± 3 years) with no cardiovascular risk factors were enrolled into this study. Vascular function and structure were assessed by flow-mediated dilation (FMD), nitroglycerin-induced vasodilation, and brachial artery intima-media thickness (baIMT) at baseline and 20 weeks after the initiation of varenicline therapy in smokers. FMD and baIMT were measured simultaneously using a semi-automatic vessel wall-tracking software program. 75 μg dose of a nitroglycerin tablet were sublingually administered for the nitroglycerin-induced vasodilation measurement.
Exhaled-carbon monoxide concentration decreased significantly (20.0 ± 11.1 ppm at baseline vs 1.9 ± 1.5 ppm after 20 weeks, p < 0.001). FMD was significantly improved after 20 weeks (4.09% ± 1.83% at baseline vs 4.77% ± 2.33% after 20 weeks, p = 0.010), whereas nitroglycerin-induced vasodilation and baIMT were not significantly changed.
Smoking cessation with varenicline therapy significantly increased FMD without significant changes of nitroglycerin-induced vasodilation or baIMT from baseline to 20 weeks. It appears to improve vascular function in smokers, which depends on endothelial function rather than on vascular smooth muscle function or changes in vascular structure.
•Plasmid was transferred into murine thigh muscles by PJI with higher efficiency than by needle.•PJI-mediated delivery of FGF2 plasmid reduced skeletal muscle injury in mice.•PJI was also applicable ...to gene transfer into murine hearts.
The angiogenic gene therapy is an attractive approach for the treatment of ischemic muscle diseases, including peripheral arterial disease and ischemic heart diseases. Although a variety of gene transfer methods have been developed, the efficiency of gene transfer is still limited. We have been developing the needleless high-energy bioinjector device, Pyro-drive Jet Injector (PJI), based on pyrotechnics using a combination of ignition powder and gunpowder, however, the utility of PJI in gene transfer into muscle tissues remains unclear. pcDNA3.1 plasmid containing Flag was injected to the thigh muscles of C57BL/6J mice using PJI or needle, as a control. Histological analysis demonstrated that the protein expression of Flag was observed in a wider range in PJI group than in needle group. To assess the validity of PJI for gene therapy, pcDNA3.1-human fibroblast growth factor 2 (FGF2), which has angiogenic activity and tissue protective properties, was injected into the ischemic thigh muscles with PJI or needle. ELISA assay revealed that the protein expression of FGF2 was increased in the thigh muscle tissues by PJI-mediated gene delivery. Significantly, histological analyses revealed that muscle fiber cross-sectional area and the number of endothelial marker CD31 (+) cells was increased in ischemic hind-limb tissues of the PJI-FGF2 group but not in those of needle-FGF2 group. To expand the applicability of the PJI-mediated gene transfer, pcDNA3.1-venus plasmid was injected into murine hearts with PJI or needle. PJI method was successful in gene transfer into murine hearts, especially into cardiomyocytes, with high efficiency when compared to needle method. Collectively, the non-needle, non-liposomal and non-viral gene transfer by PJI could be a novel therapeutic approach for muscle diseases.
In the process of lipolysis, adipocytes are stimulated by catecholamines through β1, β2, and β3 adrenergic receptors (ARs). So far, β2 and β3 AR polymorphisms have been reported related to obesity. ...However, the relation of β1AR polymorphisms to obesity has not been evaluated. In the present study, we examined whether βAR polymorphisms are associated with obesity-related phenotype in type II diabetic patients. Polymorphisms of β1Ser49Gly, β1Arg389Gly, β2Arg16Gly, β2Gln27Glu and β3Trp64Arg were genotyped in 188 type II diabetic patients by PCR-RFLP. Among these polymorphisms, β1Ser49Gly was found to be associated with obesity. Subjects with β1Gly49 allele showed higher body mass index (BMI) than those with Ser49/Ser49 genotype (24.7±3.7 vs. 23.4±3.3 kg/m2; p=0.031). Subjects with β1Gly49 allele were more frequently overweight (BMI≥25 kg/m2) compared with β1Ser49 homozygous group (42.1 vs. 24.4%, p=0.015). By multiple linear regression analysis, β1Ser49Gly polymorphism was independently associated with higher BMI (p=0.019, β=0.166). Our data indicate that the Gly49 allele in β1AR is associated with higher BMI in type II diabetic patients. Genotyping for β1Ser49Gly polymorphism in type II diabetic patients may have clinical benefit to predict obesity, thereby contributing to the prevention of insulin resistance.
Two major betalains, red-purple betacyanins and yellow betaxanthins, were isolated from red beetroots (Beta vulgaris L.), and their peroxynitrite (ONOO − ) scavenging capacity was investigated. ...Apparent colours of the betalains were bleached by the addition of ONOO − , and the absorbance decreases were suppressed in the presence of glutathione, a ONOO − scavenger. After bleaching, a new absorption maximum was observed at 350 nm in the spectrum of the resulting reaction mixture. New peaks were detected from HPLC analysis of the reaction products of betanin, a representative constituent of red beetroot betacyanins, treated with ONOO − monitoring at 350 nm, and the intensity of the major peak was positively correlated with ONOO − concentration. Betanin inhibited the ONOO − (0.5 mM)-dependent nitration of tyrosine (0.1 mM). Additionally, the IC50 value of betanin (19.2 μM) was lower than that of ascorbate (79.6 μM). The presence of betanin (0.05-1.0 mM) also inhibited ONOO − (0.5 mM)-dependent DNA strand cleavage in a concentration-dependent manner. These results suggest that betalains can protect cells from nitrosative stress in addition to protecting them from oxidative stresses.
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