Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Am J Physiol Regul Integr Comp Physiol. 2010 Aug;299(2):R683-93. doi: 10.1152/ajpregu.00162.2010. Epub 2010 May 26.
Our previous studies demonstrate that 17beta-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor alpha and beta expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-alpha (ERalpha), and ERbeta, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ERalpha expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ERbeta expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats.
我们之前的研究表明，17β-雌二醇可限制慢性容量超负荷诱导的肥厚，并改善去卵巢大鼠的心脏功能。一种可能的心脏保护机制涉及雌激素、雌激素受体和细胞外基质（ECM）蛋白之间的相互作用。使用五组雌性大鼠研究雌激素缺乏和替代对左心室（LV）肥厚和 ECM 蛋白表达的影响：完整假手术组、去卵巢假手术组、完整容量超负荷组、去卵巢容量超负荷组和去卵巢容量超负荷加雌激素治疗组。8 周后，通过 Western blot 分析评估 LV 蛋白提取物中基质金属蛋白酶-2（MMP-2）和 MMP-9、MT1-MMP、基质金属蛋白酶抑制剂（TIMP）-1、TIMP-2、TIMP-3 和 TIMP-4、胶原 I 和 III 以及雌激素受体 α 和 β 的表达。通过酶谱法评估 MMP 蛋白水解活性。所有容量超负荷组均表现出 LV 肥厚，伴有间质胶原丢失和血管周围纤维化。在 8 周的容量超负荷后，70%的去卵巢大鼠发生心力衰竭，而只有 1 只完整大鼠发生心力衰竭。在去卵巢大鼠的容量超负荷心脏中，发现 MMP-2、雌激素受体-α（ERα）和 ERβ下调，MMP-9 和 MT1-MMP 上调。雌激素治疗改善了 TIMP-2/MMP-2 和 TIMP-1/MMP-9 蛋白平衡，恢复了 ERα表达，并防止了 MMP-9 激活、血管周围胶原堆积和心力衰竭的发展。然而，雌激素并未完全恢复 ERβ表达，也未能防止 MMP-9 表达增加或间质胶原丢失。这些结果支持雌激素通过调节去卵巢大鼠容量超负荷心脏的 ECM 蛋白表达，限制不良 ECM 重塑和 LV 扩张。
