Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure
Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure
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DOI：
10.1152/ajpheart.00355.2006
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发表时间：
2007-03-01
影响因子：
4.8
通讯作者：
Trafford, A. W.
中科院分区：
文献类型：
--
作者：
Graham, H. K.;Trafford, A. W.
心肌细胞外基质（ECM）维持心肌的结构和力学完整性。我们确定了与从代偿性左心室（LV）肥大（LVH）到有症状的充血性心力衰竭（CHF）的转变相一致的ECM组成的改变以及这种变化的机制。通过主动脉结扎术在雪貂中诱导心力衰竭。采用高效液相色谱法和组织学方法测定心肌胶原含量。明胶酶谱法检测基质金属蛋白酶（MMP）活性，Western blotting法检测基质金属蛋白酶组织抑制剂（TIMP）表达。无症状LVH患者左室游离壁厚度增加29%，与间质纤维化增加20%相关（P < 0.05）。CHF与血浆血管紧张素II水平升高一致（CHF、LVH和假手术组分别为149 ± 48、40 ± 19和5.6 ± 1 pg/ml; P < 0.01，CHF vs.假手术和LVH），心室扩张（LV内径= 15 +/- 0.4 vs. 9 +/- 0.1 mm，P < 0.05），活性MMP-9增加（分别比假手术和LVH增加3.0和2.2倍，每组n = 5-10只动物，P < 0.01），并降低心肌总胶原含量（假手术组、LVH组和CHF组分别为3.5 ± 0.4、2.6 ± 0.3和2.2 ± 0.3%，P < 0.05）。在CHF中，胶原蛋白的分布明显改变，本质上变成点状。在任何时间均未发现MMP-2活性、TIMP-1、TIMP-2、TIMP-3或TIMP-4表达或胶原交联的差异。目前的工作表明，结构重组和损失的胶原蛋白从心脏ECM过渡到失代偿性CHF。MMP-9活性的增强与向CHF的转变一致，为管理从无症状LVH向有症状CHF的进展提供了潜在的治疗机会。
The cardiac extracellular matrix (ECM) maintains the structural and mechanical integrity of the myocardium. We determined the alterations in the composition of the ECM coincident with the transition from compensated left ventricular (LV) hypertrophy (LVH) to symptomatic congestive heart failure (CHF) and the mechanisms underlying such changes. Heart failure was induced in ferrets by aortic banding. Myocardial collagen content was assessed by HPLC and histological analysis. Matrix metalloproteinase (MMP) activity and tissue inhibitor of metalloproteinase (TIMP) expression were evaluated using gelatin zymography and Western blotting, respectively. LV free wall thickness increased by 29% in asymptomatic LVH and was associated with a 20% increase in interstitial fibrosis (P < 0.05). CHF was coincident with increased plasma angiotensin II levels (149 +/- 48, 40 +/- 19, and 5.6 +/- 1 pg/ml for CHF, LVH, and sham, respectively; P < 0.01, CHF vs. sham and LVH), ventricular dilatation (LV internal diameter = 15 +/- 0.4 vs. 9 +/- 0.1 mm, P < 0.05), increased active MMP-9 (3.0- and 2.2-fold increase over sham and LVH, respectively, n = 5-10 animals per group, P < 0.01), and reduced myocardial total collagen content (3.5 +/- 0.4, 2.6 +/- 0.3, and 2.2 +/- 0.3% in sham, LVH, and CHF, respectively, P < 0.05). In CHF the distribution of collagen was markedly altered, becoming punctate in nature. No difference in MMP-2 activity, TIMP-1, TIMP-2, TIMP-3, or TIMP-4 expression, or collagen cross-linking was found at any time. The present work demonstrates structural reorganization and loss of collagen from cardiac ECM during the transition to decompensated CHF. The enhanced MMP-9 activity coincident with the transition to CHF provides potential therapeutic opportunities for managing the progression from asymptomatic LVH to symptomatic CHF.