Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3.

STUDY QUESTION: What are the roles of the microRNA miR-210-an miRNA that is up-regulated in endometriotic cyst stromal cells (ECSCs)-in the pathogenesis of endometriosis? SUMMARY ANSWER: Up-regulated miR-210 expression in ECSCs is involved in their proliferation, resistance to apoptosis and angiogenesis through signal transducer and activator of transcription (STAT) 3. WHAT IS KNOWN ALREADY: In the pathogenesis of endometriosis, a number of roles for microRNAs (miRNAs) are becoming apparent. STUDY DESIGN, SIZE, DURATION: ECSCs and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues (patients aged 24-40 years undergoing salpingo-oophorectomy or evisceration for the treatment of ovarian endometriotic cysts, n = 10) and the eutopic endometrial tissues without endometriosis (premenopausal patients aged 35-45 years undergoing hysterectomies for subserousal leiomyoma, n = 13), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used a global gene expression microarray technique to identify downstream targets of miR-210, and we assessed the functions of miR-210 in the pathogenesis of endometriosis by using the miR-210-transfected NESCs. MAIN RESULTS AND THE ROLE OF CHANCE: Gene expression microarray analysis revealed that one of the key target molecules of miR-210 is STAT3. In the NESCs, in comparison to the control, miR-210 transfection resulted in the induction of cell proliferation (P < 0.0005), the production of vascular endothelial cell growth factor (VEGF) (P < 0.0005) and the inhibition of apoptosis (P < 0.05) through STAT3 activation [increased levels of mRNA (P < 0.0005), and protein (P < 0.005)]. In the ECSCs, inhibitors of STAT3 inhibited the cell proliferation and VEGF production (P < 0.05), and induced the apoptosis of these cells (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The roles of aberrant miR-210 expression were investigated only in the stromal component of ectopic and eutopic endometrium. Control endometrial tissues were obtained from premenopausal patients who had subserosal leiomyoma and NESC gene expression patterns may be altered in these women. Furthermore, the effects of STAT3 inhibitors were evaluated only in ECSCs and not in NESCs. WIDER IMPLICATIONS OF THE FINDINGS: The present findings indicate that miR-210 induces NESCs to differentiate into the endometriotic phenotype and we speculate that up-regulated miR-210 expression in ECSCs is involved in the creation of the endometriosis-specific cellular dysfunctions through epigenetic mechanisms. The data indicate that STAT3 inhibitors may be promising candidates for the treatment of endometriosis. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 25861500 to Y.K. and no. 23592407 to H.N.). There are no conflicts of interest to declare.

Noninvasive evaluation of the magnitude of aortic and mitral regurgitation by means of Doppler two-dimensional echocardiography.

Using transmitral flow velocity and left ventricular ejection flow velocity, we measured left ventricular inflow volume (LVIV) and left ventricular outflow volume (LVOV) by pulsed Doppler echocardiography in 73 patients who had mitral valve regurgitation (MR), aortic valve regurgitation (AR), or no valvular regurgitation. Doppler-determined regurgitant volume (DOPRV), Doppler-determined regurgitant fraction (DOPRF), total stoke volume, and forward stroke volume were calculated to compare the severity assessed by angiographic scoring and the regurgitant fraction determined by radionuclide angiography (RIRF). In 17 patients with MR, LVIV (84.4 +/- 20.4 ml) was significantly greater (p less than 0.01) than LVOV (52.5 +/- 15.7 ml). LVOV, which is equivalent to forward stroke volume, was lower in patients with MR (52.2 +/- 15.7 ml) than in normal subjects (67.0 +/- 15.7 ml). In 15 patients with AR, LVOV (121.7 +/- 61.1 ml) was significantly greater (p less than 0.01) than LVIV (75.1 +/- 28.1 ml) and LVOV, which is equivalent to total stroke volume, was greater in patients with AR (121.7 +/- 61.1 ml) than in normal subjects (64.0 +/- 14.4 ml). DOPRF correlated with RIRF (r = 0.79, p less than 0.01, n = 11). DOPRV (mild: 10.5 +/- 8.5 ml; moderate: 28.8 +/- 13.6 ml; severe: 74.5 +/- 36.7 ml) and DOPRF (mild: 13.7% +/- 11.5%; moderate: 33.1% +/- 14.2%; severe: 52.6% +/- 15.3%) increased markedly with the severity of regurgitation as assessed by cineangiography. In AR, total stroke volume influenced both forward stroke volume and regurgitant volume, and in MR, regurgitant volume influenced both total stroke volume and forward stroke volume. Total stroke volume in AR and regurgitant volume in MR may play a key role in valvular regurgitation.