Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart
Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart
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DOI：
10.1016/j.jacc.2003.11.058
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发表时间：
2004-05-05
影响因子：
24
通讯作者：
Hsueh, WA
中科院分区：
文献类型：
--
作者：
Collins, AR;Schnee, J;Hsueh, WA
骨桥蛋白（OPN）在左心室肥大中上调，并受到血管紧张素11（AngII）的刺激。我们的目的是确定OPN缺陷的小鼠是否能免受AngII诱导的心脏纤维化的影响。背景间质纤维化可导致心肌功能障碍并最终导致心力衰竭。骨桥蛋白激活调节细胞粘附、迁移和生长的整合素，从而暗示骨桥蛋白参与心脏纤维化的过程。方法通过渗透性微型泵向骨桥蛋白敲除（OPN-/-）小鼠（n = 18）和野生型对照（n = 20）输注AngII（2.5或3.0 μ g/kg/min）4天或3周。对心脏进行形态学和组织学评估，包括通过光学显微镜成像分析定量评估纤维化。评价这些小鼠的心脏成纤维细胞的粘附和增殖。评估细胞因子、细胞外基质（ECM）、整合素和心房利钠肽的心脏转录表达。结果：AngII灌注3周后，骨桥蛋白（-/-）小鼠的心脏纤维化（0.7%）比野生型小鼠（8.0%）少（p < 0.01），心脏/体重比（0.10% vs.0.23%）降低（p < 0.01）。转化生长因子-β、纤连蛋白和胶原蛋白的表达在OPN-/-和野生型小鼠之间没有差异，尽管OPN-/-小鼠中ECM积累减少。在OPN-/-小鼠的心脏成纤维细胞中，与ECM基质的粘附减少了30%至50%，但通过添加重组骨桥蛋白，OPN-/-细胞中的粘附得以恢复。结论：骨桥蛋白可能通过调节细胞粘附和增殖介导心肌纤维化。由于OPN在心肌肥厚中增加，而其缺乏可减弱纤维化，因此了解OPN功能对于扩展我们对心肌肥厚和心力衰竭分子决定因素的认识至关重要。（美国科尔心脏病学杂志2004;43：1698-705）（C）2004年美国心脏病学会基金会
OBJECTIVES Osteopontin (OPN) is upregulated in left ventricular hypertrophy and is stimulated by angiotensin 11 (AngII). Our objective was to determine whether mice deficient in OPN would be protected from AngII-induced cardiac fibrosis. BACKGROUND Interstitial fibrosis can lead to myocardial dysfunction and ultimately heart failure. Osteopontin activates integrins that regulate cell adhesion, migration, and growth, thus implicating OPN in the process of cardiac fibrosis. METHODS Osteopontin null (OPN-/-) mice (n = 18) and wild-type controls (n = 20) were infused with AngII (2.5 or 3.0 mug/kg/min) for four days or three weeks via osmotic mini-pumps. Hearts were assessed morphometrically and histologically, including quantitative assessment of fibrosis via optical microscopic imaging analysis. Cardiac fibroblasts derived from these mice were evaluated for adhesion and proliferation. Cardiac transcript expression for cytokines, extracellular matrix (ECM), integrin, and atrial natriuretic peptide were assessed. RESULTS Osteopontin(-/-) mice exhibited less cardiac fibrosis (0.7%) than wild-type mice (8.0%) (p < 0.01) and lowered heart/body weight ratios (0.10% vs. 0.23%) (p < 0.01) after three weeks of AngII infusion. Expression of transforming growth factor-beta, fibronectin, and collagen was not different between OPN-/- and wild-type mice, despite the decrease in ECM accumulation in the OPN-/- mice. Adhesion to ECM substrates decreased by 30% to 50% in cardiac fibroblasts of OPN-/- mice but was restored in OPN-/- cells by the addition of recombinant osteopontin. CONCLUSIONS Osteopontin mediates cardiac fibrosis, probably through the modulation of cellular adhesion and proliferation. Because OPN is increased in cardiac hypertrophy and its lack attenuates fibrosis, understanding of OPN function is essential to extend our knowledge about molecular determinants of cardiac hypertrophy and failure. (J Am Coll Cardiol 2004;43:1698-705) (C) 2004 by the American College of Cardiology Foundation