Dai Qiuxia, Lin Jing, Craig Teresa, Chou Youn-Min, Hinojosa-Laborde Carmen, Lindsey Merry L
Department of Medicine/Cardiology, University of Texas Health Science Center, San Antonio,TX 78229-3900, USA.
Gend Med. 2008 Mar;5(1):74-85. doi: 10.1016/s1550-8579(08)80010-1.
Female Dahl salt-sensitive (DS) rats fed a low-salt diet develop hypertension at 6 months of age. Ovariectomy at 2 months of age accelerates the development of hypertension, and estrogen replacement delays it. Although acute pressure overload induces structural changes in the left ventricle (LV) further effects of gradual hypertension on LV remodeling have not been examined in the DS rat model.
The purpose of this study was to test the hypothesis that aging and estrogen loss in hypertensive DS rats are accompanied by changes in LV remodeling.
Four groups of DS rats were examined: young intact, middle-aged (MA) intact, MA ovariectomized (MA-OVX), and MA-OVX with 17beta-eestradiol (E(2)) supplementation (MA-OVX+E(2)). Myocardial matrix metalloproteinases (MMPs),tissue inhibitors of metalloproteinases (TIMPs),and extracellular matrix (ECM) proteins were assessed by immunoblotting.
Each of the 4 groups comprised 6 animals. Mean (SEM) LV mass was significantly greater in the MA-intact and the MA-OVX groups (1257 [31] mg and 1199 [25] mg, respectively; both, P < 0.05) compared with the young-intact group (697 [6] mg). LV mass in the MA-OVX+E(2) group was significantly lower compared with the MA-intact and MA-OVX groups (both, P < 0.05), suggesting that estrogen may attenuate LV remodeling. Fibronectin and collagen III and IV concentrations increased significantly in the MA-intact and MA-OOVX groups (all, P < 0.05),indicating increased fibrosis. Multiple MMPs also increased in the MA-intact an nd MA-OVX rats, including MMP-3, -7, -99, -113, and -114, and all TIMPs. In contrast, estrogen attenuated fibrosis by increasing MMP-8 concentrations and increasing collagen III fragments. From good-fit regression modeling, MMP-13 and MMP-14 concentrations correlated positively with LV mass for the MA-intact and MA-OVX groups, respectively.
Gradual hypertension stimulated ECM turnover by increasing both MMP/TIMP production and ECM degradation. Estrogen loss or gain resulted in a shift in MMP profiles, suggesting that MMP-13 and MMP-14 may be differentially regulated in postmenopausal hypertension.
喂食低盐饮食的雌性 Dahl 盐敏感（DS）大鼠在 6 个月大时会患上高血压。2 个月大时进行卵巢切除术会加速高血压的发展，而雌激素替代则会延缓其发展。尽管急性压力超负荷会导致左心室（LV）发生结构变化，但在 DS 大鼠模型中尚未研究逐渐发展的高血压对 LV 重塑的进一步影响。
本研究的目的是验证以下假设：高血压 DS 大鼠的衰老和雌激素丧失伴随着 LV 重塑的变化。
检查了四组 DS 大鼠：年轻未切除卵巢组、中年（MA）未切除卵巢组、MA 卵巢切除组（MA-OVX）以及补充 17β-雌二醇（E₂）的 MA-OVX 组（MA-OVX+E₂）。通过免疫印迹法评估心肌基质金属蛋白酶（MMPs）、金属蛋白酶组织抑制剂（TIMPs）和细胞外基质（ECM）蛋白。
四组每组包含 6 只动物。与年轻未切除卵巢组（697 [6] mg）相比，MA 未切除卵巢组和 MA-OVX 组的平均（SEM）LV 质量显著更高（分别为 1257 [31] mg 和 1199 [25] mg；均 P < 0.05）。MA-OVX+E₂ 组的 LV 质量与 MA 未切除卵巢组和 MA-OVX 组相比显著更低（均 P < 0.05），表明雌激素可能会减轻 LV 重塑。纤维连接蛋白以及胶原蛋白 III 和 IV 的浓度在 MA 未切除卵巢组和 MA-OVX 组中显著增加（均 P < 0.05），表明纤维化增加。多种 MMPs 在 MA 未切除卵巢组和 MA-OVX 大鼠中也增加，包括 MMP-3、-7、-99、-113 和 -114，以及所有 TIMPs。相比之下，雌激素通过增加 MMP-8 浓度和增加胶原蛋白 III 片段来减轻纤维化。通过良好拟合回归模型，MMP-13 和 MMP-14 浓度分别与 MA 未切除卵巢组和 MA-OVX 组的 LV 质量呈正相关。
逐渐发展的高血压通过增加 MMP/TIMP 产生和 ECM 降解来刺激 ECM 周转。雌激素的丧失或增加导致 MMP 谱的改变，表明 MMP-13 和 MMP-14 在绝经后高血压中可能受到不同的调节。
