Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis
Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis
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DOI：
10.1007/s00109-004-0606-4
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发表时间：
2004-12-01
影响因子：
4.7
通讯作者：
Regitz-Zagrosek, V
中科院分区：
文献类型：
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作者：
Fielitz, J;Leuschner, M;Regitz-Zagrosek, V
主动脉瓣狭窄（AS）导致人左心室（LV）中的肌细胞和细胞外基质重构。心肌肾素-血管紧张素系统被激活，胶原蛋白I和III以及纤连蛋白积聚。我们确定了控制胶原蛋白周转的酶的未知调节，即，左室基质金属蛋白酶（MMP）及其组织抑制剂（TIMPs）在人类AS中的作用。我们比较了接受选择性主动脉瓣置换术的AS患者C17（n=19）与LV功能正常的未使用供体心脏（对照组，n=12）的LV样本。采用实时荧光定量PCR法检测MMP-2、MMP-9、MT 1-MMP、细胞外基质金属蛋白酶诱导因子（EMMPRIN）、TIMP-1、TIMP-2、TIMP-3和TIMP-4 mRNA的表达。MMP-1、MMP-2、MMP-3。TIMP-3、TIMP-4和EMMPRIN蛋白用免疫印迹法测定，MMP-9和TIMP-1蛋白用ELISA法测定。酶谱法测定明胶酶MMP-2和MMP-9活性。MMP-2在mRNA、蛋白质和活性水平上在AS中增加（对照组的131%、193%和138%）。MMP-3蛋白（308%）、EMMPRIN mRNA和蛋白（171%和200%）也上调。相反，MMP-1（37%）和MMP-9的mRNA，蛋白质和活性（26%，21%和52%）下调。MMP-9活性与LV大小呈负相关。TIMP-1 mRNA和蛋白表达降低（55%和73%）。而TIMP-2 mRNA（358%）、TIMP-3 mRNA和蛋白（145%和249%）则明显升高。TIMP-4 mRNA无改变，但TIMP-4蛋白上调至350%。左室射血分数正常和受损的AS患者的变化相似。在人类AS中，心肌MMPs和TIMPs的失调开始于LV功能仍然正常的早期疾病阶段。尽管一些MMP的C上调，但MMP和TIMP之间的平衡在人AS中向MMP抑制转移，并且可能有助于胶原积累。
Aortic stenosis (AS) results in myocyte and extracellular matrix remodeling, in the human left ventricle (LV). The myocardial renin-angiotensin system is 14 activated and collagens I and III and fibronectin accumulate. We determined the yet unknown regulation of enzymes that control collagen turnover, i.e., LV matrix metalloproteinases (MMP) and their tissue inhibitors (TIMPs) in human AS. We compared LV samples from AS patients undergoing elective aortic valve replacement C 17 (n=19) with nonused donor hearts with normal LV function (controls, n=12). MMP-2, MMP-9, MT1-MMP, and extracellular matrix rnetalloproteinase inducer (EMMPRIN), TIMP-1, TIMP-2, TIMP-3, and TIMP-4 mRNA were quantitated by real-time RCR. MMP-1, MMP-2, MMP-3. TIMP-3, TIMP-4, and EMMPRIN protein were measured by immunoblotting and MMP-9 and TIMP-1 protein by ELISA. Gelatinolytic MMP-2 and MMP-9 activity was measured by zymography. MMP-2 was increased in AS at mRNA, protein, and activity levels (131% 193%, and 138% of controls). MMP-3 protein (308%) and EMMPRIN mRNA and protein were also upregulated (171% and 200%). In contrast, MMP-1 (37%) and MMP-9 mRNA, protein, and activity (26%, 21%, and 52%) were downregulated. MMP-9 activity was inversely correlated with LV size. TIMP-1 mRNA and protein were decreased (55% and 73%). In contrast, TIMP-2 mRNA (358%), TIMP-3 mRNA and protein (145% and 249%) were increased. TIMP-4 mRNA was not altered, but TIMP-4 protein was upregulated to 350%. Changes were similar in AS patients with normal and impaired LV ejection fraction. The dysregulation of myocardial MMPs and TIMPs in human AS starts at an early disease stage when LV function is still normal. In spite of upregulation C of some MMPs the balance between MMP and TIMP is shifted towards MMP inhibition in human AS and may contribute to collagen accumulation.