Adverse Biventricular Remodeling in Isolated Right Ventricular Hypertension Is Mediated by Increased Transforming Growth Factor-β1 Signaling and Is Abrogated by Angiotensin Receptor Blockade
Adverse Biventricular Remodeling in Isolated Right Ventricular Hypertension Is Mediated by Increased Transforming Growth Factor-β1 Signaling and Is Abrogated by Angiotensin Receptor Blockade
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DOI：
10.1165/rcmb.2013-0149oc
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发表时间：
2013-12-01
影响因子：
6.4
通讯作者：
Redington, Andrew N.
中科院分区：
文献类型：
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作者：
Friedberg, Mark K.;Cho, Mi-Young;Redington, Andrew N.
压力负荷的右心室（RV）对左心室（LV）功能有不利影响。我们最近发现，这些心室-心室相互作用通过转化生长因子β 1（TGF-β 1）信号传导导致LV心肌纤维化。我们研究了RV后负荷介导双心室纤维化的机制及其通过血管紧张素受体阻滞剂的潜在修饰。在家兔体内放置可调节的肺动脉带（PAB）。在假手术对照兔中，带保持未充气（n = 6）。在RV后负荷组中，在第28天连续充盈PAB以产生全身RV压力（n = 8）。在第三组中，PAB膨胀至全身水平，并加入血管紧张素受体阻滞剂氯沙坦（n = 6）。手术后5周，处死动物以评估双心室肥大、纤维化、细胞凋亡及其信号通路的组分。PAB动物与假手术兔相比，出现了双心室肥大、纤维化和细胞凋亡，而这些情况在氯沙坦治疗后有所减轻。PA B动物的RV和LV TGF-β 1、结缔组织生长因子（CTGF）（CCN 2）、内皮素-1（ET-1）、内皮素受体B和基质金属蛋白酶2/9 mRNA水平均高于假手术动物，而氯沙坦组降低。鉴于PAB中显著的双心室CTGF上调和氯沙坦的下调，我们研究了CTGF信号传导。PAB组RV和LV Smad 2/3/4蛋白水平和LV RhoA mRNA水平升高，氯沙坦组降低。总之，孤立的RV后负荷诱导双心室纤维化和细胞凋亡，血管紧张素受体阻滞剂减少。由孤立RV后负荷诱导的不良心室-心室相互作用似乎通过TGF-β 1-CTGF和ET-1途径介导。
The pressure-loaded right ventricle (RV) adversely affects left ventricular (LV) function. We recently found that these ventricular-ventricular interactions lead to LV myocardial fibrosis through transforming growth factor-beta 1 (TGF-beta 1) signaling. We investigated the mechanisms mediating biventricular fibrosis in RV afterload and their potential modification by angiotensin receptor blockade. An adjustable pulmonary artery band (PAB) was placed in rabbits. In sham-operated control rabbits, the band was left uninflated (n = 6). In the RV afterload group, the PAB was sequentially inflated to generate systemic RV pressure at 28 days (n = 8). In a third group, the PAB was inflated to systemic levels, and the angiotensin receptor blocker losartan was added (n = 6). Five weeks after surgery, the animals were killed for assessments of biventricular hypertrophy, fibrosis, apoptosis, and the components of their signaling pathways. PAB animals developed biventricular hypertrophy, fibrosis, and apoptosis, versus sham rabbits, in which these conditions were decreased with losartan. RV and LV TGF-beta 1, connective tissue growth factor (CTGF) (CCN2), endothelin-1 (ET-1), endothelin receptor B, and matrix metalloproteinase 2/9 mRNA levels were increased in PAB animals versus sham animals, and decreased with losartan. Given the marked biventricular CTGF up-regulation in PAB and down-regulation with losartan, we investigated CTGF signaling. RV and LV Smad 2/3/4 protein levels and LV RhoA mRNA levels were increased with PAB and reduced with losartan. In conclusion, isolated RV afterload induces biventricular fibrosis and apoptosis, which are reduced by angiotensin receptor blockade. Adverse ventricular-ventricular interactions induced by isolated RV afterload appear to be mediated through TGF-beta 1-CTGF and ET-1 pathways.