Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects
Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects
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DOI：
10.1152/ajpheart.00317.2005
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发表时间：
2005-12-01
影响因子：
4.8
通讯作者：
Greenberg, BH
中科院分区：
文献类型：
--
作者：
Iwata, M;Cowling, RT;Greenberg, BH
ANG-（1-7）改善重构心脏的功能。虽然这种肽直接在心肌内产生，但ANG-（1-7）对心脏成纤维细胞的影响在很大程度上是未知的，而心脏成纤维细胞在心脏重塑中起着关键作用。我们检验了ANG-（1-7）与心脏成纤维细胞特异性结合调节心脏重塑相关细胞功能的假设。I-125标记的ANG-（1-7）结合试验鉴定了ANG-（1-7）在成年大鼠心脏成纤维细胞（ARCF）上的特异性结合位点，亲和力为11.3 nM，密度为131 fmol/mg蛋白。在纳摩尔浓度下，ANG-（1-7）与不同于ANG II 1型和2型受体的特异性位点相互作用，而不增加胞浆Ca 2+浓度。在这些浓度下，ANG-（1-7）通过[H-3]脯氨酸掺入和ARCF中生长因子mRNA表达的降低来评估对胶原合成的抑制作用。ANG-（1-7）的这些作用与ANG II的作用相反。用ANG-（1-7）预处理ARCF可抑制ANG II诱导的胶原合成增加和生长因子（包括内皮素-1和白血病抑制因子）mRNA表达增加。ANG-（1-7）预处理还抑制ANG II处理的ARCF的条件培养基对心肌细胞中[H-3]亮氨酸掺入和心房利钠因子mRNA表达（肥大标志物）的刺激作用。因此，ANG-（1-7）与ARCF上的特异性受体相互作用，发挥潜在的抗纤维化和抗营养作用，可逆转ANG II的作用。提示ANG-（1-7）在心脏重构中起重要作用。
ANG-(1-7) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(1-7) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(1-7) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. I-125-labeled ANG-(1-7) binding assays identified specific binding sites of ANG-(1-7) on adult rat cardiac fibroblasts (ARCFs) with an affinity of 11.3 nM and a density of 131 fmol/mg protein. At nanomolar concentrations, ANG-(1-7) interacted with specific sites that were distinct from ANG II type 1 and type 2 receptors without increasing cytosolic Ca2+ concentration. At these concentrations, ANG-(1-7) had inhibitory effects on collagen synthesis as assessed by [H-3] proline incorporation and decreased mRNA expression of growth factors in ARCFs. These effects of ANG-(1-7) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(1-7) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(1-7) pretreatment also inhibited the stimulatory effects of conditioned medium from ANG II-treated ARCFs on [H-3] leucine incorporation and atrial natriuretic factor mRNA expression, markers of hypertrophy, in cardiomyocytes. Thus ANG-(1-7) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(1-7) may play an important role in the heart in regulating cardiac remodeling.