Endothelial S1pr1 regulates pressure overload‐induced cardiac remodelling through AKT‐eNOS pathway

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.     

Genome-wide analysis of mammalian DNA segment fusion/fission

As a powerful tool for gene function prediction, gene fusion has been widely studied in prokaryotes and certain groups of eukaryotes, but it has been little applied in studies of mammalian genomes. With the first fully sequenced mammalian genomes (human, mouse, rat) now available, we defined and collected a set of fusion/fission event-linked segments (FFLS) based on structured organized genomic alignment. The statistics of the sequence features highlighted the FFLSs against their random context. We found that there are three groups of FFLSs with different component pairs (i.e. gene-gene, gene-noncoding and noncoding-noncoding) in all three mammalian genomes. The proteins encoded by the components of FFLSs in the first group shown a strong tendency to interact with each other. The segmental components in the last two groups which did not contain any protein-coding genes, were found not only to be transcribed to some level, but also more conserved than the random background. Thus, these segments are possibly carrying certain biologically functional elements. We propose that FFLS may be a potential tool for prediction and analysis of function and functional interaction of genetic elements, including both genes and noncoding elements, in mammalian genomes. The full list of the FFLSs in the genomes of the three mammals is available as supporting information at doi:10.1016/j.jtbi.2005.09.016.     

VO(2) kinetics reveal a central limitation at the onset of subthreshold exercise in heart transplant recipients.

Because the cardiocirculatory response of heart transplant recipients (HTR) to exercise is delayed, we hypothesized that their O(2) uptake (VO(2)) kinetics at the onset of subthreshold exercise are slowed because of an impaired early "cardiodynamic" phase 1, rather than an abnormal subsequent "metabolic" phase 2. Thus we compared the VO(2) kinetics in 10 HTR submitted to six identical 10-min square-wave exercises set at 75% (36 +/- 5 W) of the load at their ventilatory threshold (VT) to those of 10 controls (C) similarly exercising at the same absolute (40 W; C40W group) and relative load (67 +/- 14 W; C67W group). Time-averaged heart rate, breath-by-breath VO(2), and O(2) pulse (O(2)p) data yielded monoexponential time constants of the VO(2) (s) and O(2)p increase. Separating phase 1 and 2 data permitted assessment of the phase 1 duration and phase 2 VO(2) time constant (). The VO(2) time constant was higher in HTR (38.4 +/- 7.5) than in C40W (22.9 +/- 9.6; P < or = 0. 002) or C67W (30.8 +/- 8.2; P < or = 0.05), as was the O(2)p time constant, resulting from a lower phase 1 VO(2) increase (287 +/- 59 vs. 349 +/- 66 ml/min; P < or = 0.05), O(2)p increase (2.8 +/- 0.6 vs. 3.6 +/- 1.0 ml/beat; P < or = 0.0001), and a longer phase 1 duration (36.7 +/- 12.3 vs. 26.8 +/- 6.0 s; P < or = 0.05), whereas the was similar in HTR and C (31.4 +/- 9.6 vs. 29.9 +/- 5.6 s; P = 0.85). Thus the HTR have slower subthreshold VO(2) kinetics due to an abnormal phase 1, suggesting that the heart is unable to increase its output abruptly when exercise begins. We expected a faster in HTR because of their prolonged phase 1 duration. Because this was not the case, their muscular metabolism may also be impaired at the onset of subthreshold exercise.     

Modified Long Wavelength Approximation for the Optical Response of a Graded-Index Plasmonic Nanoparticle

The optical response of graded-index spherical metallic nanoparticles is studied in the modified long wavelength approximation with electrodynamic effects accounted for to the lowest order of the inverse of the wavelength. An effective-medium approach is adopted which leads to the conclusion that the first-order dynamical effects will enter mainly via the polarizability and not the effective dielectric function of the system. Numerical studies using various graded Drude functions show that these effects are not only significant for particles of large sizes but can also be appreciable for smaller particles with varying index profile.     

Expression of apoptosis-related genes in the endometrium of polycystic ovary syndrome patients during the window of implantation

The present study investigated the expression of the apoptosis-related genes fas-associated via death domain (FADD) and Bcl-2 in the endometrium during the window of implantation in polycystic ovary syndrome (PCOS) patients. The aim was to explore the role of cell apoptosis in endometrial receptivity during this period. The subjects were divided into experimental and control group. The experimental group comprised 12 infertile women with PCOS, and the control group comprised 12 women who were infertile because of tubal pathological factors but had normal menstrual cycles. Endometria were collected by biopsy 7d after ovulation. Six samples from each group were randomly selected and subjected to gene chip analyses. The expression of endometrial FADD and Bcl-2 was determined by immunohistochemistry, and cell apoptosis was detected by the TUNEL method. Compared with the control group, 194 differentially expressed genes were found in the PCOS group, 102 of which were upregulated and 92 were downregulated. The differentially expressed genes were divided into 15 types according to function. Among the nine genes related to cell apoptosis, five (including Bcl-2) were upregulated and four were downregulated (including FADD). Bcl-2 expression during the window of implantation in the PCOS group increased compared with the control group, showing a significant difference (P<0.05). FADD expression in the PCOS group notably decreased compared with that in the control group, which also showed a significant difference (P<0.05). Cell apoptosis analysis showed a significant difference between the average apoptotic indices in the PCOS and control groups (P<0.05). Significant differences were observed between the endometrial gene expression in the PCOS and control groups. The decrease in cell apoptosis during the window of implantation in PCOS patients may be one of the causes of the reduced endometrial receptivity.