Murray David B, Gardner Jason D, Brower Gregory L, Janicki Joseph S
University of South Carolina, School of Medicine, Department of Cell and Developmental Biology and Anatomy, Columbia, SC 29208, USA.
Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1251-7. doi: 10.1152/ajpheart.00622.2007. Epub 2008 Jan 4.
The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg.kg(-1).day(-1))-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 +/- 0.3 vs. 1.3 +/- 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P <or= 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 +/- 0.3 vs. 0.9 +/- 0.1 arbitrary activity units, Fist vs. Fist + Bos, P <or= 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 +/- 0.1 vs. 0.8 +/- 0.1% myocardial tissue, Sham vs. Fist, P <or= 0.01) was significantly attenuated following bosentan treatment at both the 1- and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.
本研究的目的是调查非选择性内皮素 -1（ET-1）受体拮抗剂（波生坦）对急性心肌重塑过程的影响，包括继发于容量超负荷的左心室（LV）肥大细胞和基质金属蛋白酶（MMP）活性。此外，我们研究了在慢性容量超负荷14天期间预防性内皮素受体拮抗作用的整体功能结果。在建立主动脉腔静脉瘘后1天和5天，分析假手术（Sham）、未治疗的瘘管（Fist）和波生坦（100 mg·kg-1·d-1）治疗的动物（Fist + Bos）的LV组织中的肥大细胞密度、MMP活性和心肌胶原容积分数。与未治疗的瘘管相比，波生坦治疗可预防瘘管后1天LV肥大细胞密度的显著增加（3.1±0.3对1.3±0.3个LV肥大细胞/mm2，Fist对Fist + Bos，P≤0.01）。此外，波生坦治疗可预防未治疗的瘘管在1天时MMP-2激活的大幅增加（1.6±0.3对0.9±0.1任意活性单位，Fist对Fist + Bos，P≤0.01）。Fist组中观察到的胶原容积分数的显著降低（1.4±0.1对0.8±0.1%心肌组织，Sham对Fist，P≤0.01）在波生坦治疗后的1天和5天时间点均得到显著缓解。最后，与未治疗的瘘管心脏相比，波生坦的2周预防性治疗导致LV收缩末期和舒张末期容积增加的显著减轻。总之，非选择性ET-1拮抗作用可预防继发于慢性容量超负荷引起的心脏肥大细胞密度和MMP激活的急性增加。通过预防这些事件，ET-1拮抗作用有效地减轻了心室扩张，并限制了慢性容量超负荷前2周结构和功能缺陷的发展。因此，这些结果首次证明心脏肥大细胞在体内对内源性内皮素系统有反应。本研究的另一个新发现是，慢性非特异性内皮素拮抗作用可能无意中增强ET-1介导的信号传导。
