雌激素逆转重度肺动脉高压时右心室结构和细胞外基质重塑。
Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension.
机构信息
Department of Anesthesiology, Division of Molecular Medicine, University of California at Los Angeles, Los Angeles, California 90095-7115, USA.
出版信息
J Appl Physiol (1985). 2012 Jul;113(1):149-58. doi: 10.1152/japplphysiol.01349.2011. Epub 2012 May 24.
Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β.
慢性肺动脉高压（PH）可导致右心室衰竭（RVF），其特征为 RV 重构。心室重构在心力衰竭及其恢复过程中是一个重要的过程。PH 诱导的 RVF 中的重构尚未完全了解。最近，我们发现雌激素（E2）治疗可以挽救严重的预先存在的 PH。在这里，我们专注于 E2（42.5μg·kg(-1)·天(-1)，10 天）是否可以逆转使用单环酸（MCT，60mg/kg）引起的 PH 引起的 RV 结构和细胞外基质（ECM）重构的不良影响。RV 纤维化在 RVF 男性中很明显。完整的女性与男性和去卵巢（OVX）女性相比，RV 重构的严重程度较低。新型 ECM 降解解整合素金属蛋白酶 ADAM15 和 ADAM17 转录本在所有 RVF 动物中均升高约 2 倍。E2 治疗可逆转所有组的 RV 重构。在体外，E2 直接抑制 ANG II 诱导的纤维化标志物以及培养的心肌成纤维细胞中的金属蛋白酶的表达。雌激素受体-β激动剂二芳基丙腈（DPN）而不是雌激素受体-α激动剂 4,4',4″-(4-丙基-[1H]-吡唑-1,3,5-三基)三苯酚（PPT）与 E2 一样有效抑制这些基因的表达。细胞外基质相互作用的胎儿心脏基因骨桥蛋白（OPN）的表达在 RVF 男性中也增加了约 9 倍。完整的女性部分免受 OPN 上调（约 2 倍）的保护，但 OVX 女性则没有。E2 逆转了所有组中的 OPN 上调。E2 在体外也逆转了 OPN 的上调。RVF 中的血浆 OPN 升高（约 1.5 倍），E2 组降低至对照水平。RVF 导致 RV 中 Akt 磷酸化升高，但 ERK 不升高，E2 治疗恢复了 Akt 磷酸化。总之，E2 治疗通过逆转纤维化和上调新型 ECM 酶 ADAM15、ADAM17 和 OPN 来逆转与 PH 相关的不良 RV 重构。这些作用可能是通过雌激素受体-β介导的。
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