Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload
Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload
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DOI：
10.1161/01.hyp.0000208840.30778.00
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发表时间：
2006-04-01
期刊：
影响因子：
8.3
通讯作者：
Tsutsui, H
中科院分区：
文献类型：
--
作者：
Matsusaka, H;Ide, T;Tsutsui, H
基质金属蛋白酶（MMPs）在细胞外基质重塑中起着重要作用。实验和临床研究表明，mmp2和mmp9在扩张衰竭心脏中表达上调，参与心肌重构的发生和进展。然而，对于MMPs在慢性压力过载（PO）时介导不良心肌重构中的作用，我们知之甚少。因此，我们假设选择性破坏MMP 2基因可以改善po诱导的小鼠心脏肥厚和功能障碍。雄性MMP 2基因敲除（KO）小鼠（n = 10）和兄弟姐妹野生型（WT）小鼠（n = 9）经主动脉横缩（TAC）诱导PO肥厚。6周时，WT + TAC组心肌MMP 2酶谱活性增加2.4倍，KO + TAC组未观察到这种增加，其他MMPs （MMP 1、3、8和9）或MMPs的组织抑制剂（1、2、3和4）没有明显改变。TAC导致左室（LV）重量和左室舒张末压（EDP）显著增加，并保留收缩功能。与WT + TAC小鼠相比，KO + TAC小鼠的左室重量/体重（4.2 +/- 0.2 vs 5.0 +/- 0.2 mg/ g, P < 0.01）、肺重量/体重（4.9 +/- 0.2 vs 6.2 +/- 0.4 mg/ g, P < 0.01）和左室舒张末期压（4 +/- 1 vs 10 +/- 2 mmhg, P < 0.05）明显低于WT + TAC小鼠，尽管主动脉压相当。KO + TAC小鼠心肌细胞肥大较少(横截面积：322 +/- 14 μ m比392 +/- 14 μ m(2)；P < 0.01)和间质纤维化（胶原体积分数：3.3 +/- 0.5比8.2 +/- 1.0%,P < 0.01）。mmp2在po诱导的左室肥大和功能障碍中起重要作用。因此，抑制MMP 2的激活可能是一种有效的治疗高血压心脏病的策略。
Matrix metalloproteinases ( MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload ( PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction ( TAC) in male MMP 2 knockout ( KO) mice ( n = 10) and sibling wild-type ( WT) mice ( n = 9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4- fold increased in WT + TAC, and this increase was not observed in KO + TAC, with no significant alterations in other MMPs ( MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs ( 1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular ( LV) weight and LV end-diastolic pressure ( EDP) with preserved systolic function. KO + TAC mice exerted significantly lower LV weight/body weight ( 4.2 +/- 0.2 versus 5.0 +/- 0.2 mg/ g; P < 0.01), lung weight/body weight ( 4.9 +/- 0.2 versus 6.2 +/- 0.4 mg/ g; P < 0.01), and LV end-diastolic pressure ( 4 +/- 1 versus 10 +/- 2 mm Hg; P < 0.05) than WT + TAC mice despite comparable aortic pressure. KO + TAC mice had less myocyte hypertrophy ( cross-sectional area; 322 +/- 14 versus 392 +/- 14 mu m(2); P < 0.01) and interstitial fibrosis ( collagen volume fraction; 3.3 +/- 0.5 versus 8.2 +/- 1.0%; P < 0.01) than WT + TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.