Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain.
Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain.
Cells. 2020 Mar 30;9(4):833. doi: 10.3390/cells9040833.
Pressure overload in patients with aortic stenosis (AS) induces an adverse remodeling of the left ventricle (LV) in a sex-specific manner. We assessed whether a sex-specific miR-29b dysregulation underlies this sex-biased remodeling pattern, as has been described in liver fibrosis. We studied mice with transverse aortic constriction (TAC) and patients with AS. miR-29b was determined in the LV (mice, patients) and plasma (patients). Expression of remodeling-related markers and histological fibrosis were determined in mouse LV. Echocardiographic morpho-functional parameters were evaluated at baseline and post-TAC in mice, and preoperatively and 1 year after aortic valve replacement (AVR) in patients with AS. In mice, miR-29b LV regulation was opposite in TAC-males (down-regulation) and TAC-females (up-regulation). The subsequent changes in miR-29b targets (collagens and GSK-3β) revealed a remodeling pattern that was more fibrotic in males but more hypertrophic in females. Both systolic and diastolic cardiac functions deteriorated more in TAC-females, thus suggesting a detrimental role of miR-29b in females, but was protective in the LV under pressure overload in males. Clinically, miR-29b in controls and patients with AS reproduced most of the sexually dimorphic features observed in mice. In women with AS, the preoperative plasma expression of miR-29b paralleled the severity of hypertrophy and was a significant negative predictor of reverse remodeling after AVR; therefore, it may have potential value as a prognostic biomarker.
主动脉瓣狭窄（AS）患者的压力超负荷以性别特异性方式诱导左心室（LV）的不利重构。我们评估了 miR-29b 的性别特异性失调是否是这种性别偏向性重构模式的基础，正如在肝纤维化中所描述的那样。我们研究了横主动脉缩窄（TAC）的小鼠和 AS 患者。在 LV（小鼠，患者）和血浆（患者）中测定了 miR-29b。在小鼠 LV 中测定了与重构相关的标志物的表达和组织纤维化。在 TAC 后评估了小鼠的超声心动图形态功能参数，在 AS 患者的主动脉瓣置换（AVR）术前和 1 年后评估了患者的术前和 1 年后。在小鼠中，miR-29b 的 LV 调节在 TAC 雄性（下调）和 TAC 雌性（上调）中相反。miR-29b 靶标（胶原和 GSK-3β）的随后变化揭示了一种在雄性中更纤维化但在雌性中更肥大的重构模式。TAC 雌性的收缩和舒张心脏功能恶化更多，因此表明 miR-29b 在雌性中起有害作用，但在雄性中在压力超负荷下对 LV 起保护作用。临床上，miR-29b 在对照和 AS 患者中复制了在小鼠中观察到的大多数性别二态性特征。在 AS 女性中，miR-29b 的术前血浆表达与肥大的严重程度平行，并且是 AVR 后反向重构的显著负预测因子；因此，它可能具有作为预后生物标志物的潜在价值。
