Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval / Québec Heart and Lung Institute, Université Laval, Québec city, Canada.
Physiol Rep. 2022 Aug;10(16):e15433. doi: 10.14814/phy2.15433.
The lesions observed in AS have been shown to be sex specific, with women presenting extensive fibrotic remodeling while men developing more calcification deposit. We thus aimed to evaluate the influence of sex and sex hormones on the pathophysiology of aortic valve stenosis (AS) in our mouse model of AS. LDLr ApoB IGF-II mice (n = 210) were separated in six different groups: (1) intact male (IM), (2) intact female (IF), (3) castrated male (CM), (4) ovariectomized females (OF), (5) CM with testosterone supplementation (CMT), and (6) OF with 17β-estradiol supplementation (OFE). Mice were fed a high-fat/high-sucrose/high-cholesterol diet for 6 months. Hemodynamic progression of AS was followed by transthoracic echocardiography (at 12 and 36 weeks) and analyzed in all mice alive at 36 weeks. Aortic valves were collected for histological and digital droplet PCR* analysis. Increases in peak velocity were comparable in IF and IM (24.2 ± 5.7 vs. 25.8 ± 5.3 cm/s; p = 0.68), but IF presented with less severe AS. Between the three groups of male mice, AS progression was more important in IM (increase in peak velocity: 24.2 ± 5.7 cm/s; p < 0.001) compared to CM (6.2 ± 1.4; p = 0.42), and CMT (15.1 ± 3.5; p = 0.002). In the three groups of female mice, there were no statistical differences in AS progression. Digital PCR analysis revealed an important upregulation of the osteogenic gene RunX2 in IM (p < 0.0001) and downregulation of the pro-calcifying gene ALPL in IF (p < 0.05). Male sex and testosterone play an important role in upregulation of pro-calcifying genes and hemodynamic progression of AS. However, female mice appeared to be protected against calcification, characterized by downregulation of pro-osteogenic genes, but presented a similar AS hemodynamic progression.
在 AS 中观察到的病变已被证明具有性别特异性，女性表现出广泛的纤维化重塑，而男性则发展出更多的钙化沉积。因此，我们旨在评估性别和性激素对我们的 AS 小鼠模型中主动脉瓣狭窄 (AS) 病理生理学的影响。LDLr ApoB IGF-II 小鼠（n=210）分为六个不同的组：（1）完整雄性（IM），（2）完整雌性（IF），（3）去势雄性（CM），（4）卵巢切除雌性（OF），（5）CM 补充睾酮（CMT），和（6）OF 补充 17β-雌二醇（OFE）。小鼠接受高脂肪/高蔗糖/高胆固醇饮食 6 个月。通过经胸超声心动图（12 周和 36 周）监测 AS 的血流动力学进展，并在 36 周时分析所有存活的小鼠。收集主动脉瓣进行组织学和数字液滴 PCR*分析。IF 和 IM 的峰值速度增加相当（24.2±5.7 vs. 25.8±5.3 cm/s；p=0.68），但 IF 表现出较轻的 AS。在三组雄性小鼠中，IM 的 AS 进展更为严重（峰值速度增加：24.2±5.7 cm/s；p<0.001），而 CM（6.2±1.4；p=0.42）和 CMT（15.1±3.5；p=0.002）。在三组雌性小鼠中，AS 进展没有统计学差异。数字 PCR 分析显示，IM 中骨形成基因 RunX2 的重要上调（p<0.0001）和 IF 中促钙化基因 ALPL 的下调（p<0.05）。雄性性别和睾酮在促钙化基因的上调和 AS 的血流动力学进展中起着重要作用。然而，雌性小鼠似乎受到保护而免于钙化，其特征是促成骨基因下调，但表现出类似的 AS 血流动力学进展。
