Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Tecnológicas of Argentina, Argentina.
Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H1003-13. doi: 10.1152/ajpheart.00803.2009. Epub 2010 Jan 8.
The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.
本研究旨在探讨血管紧张素(ANG)-(1-7)的慢性治疗是否能减轻果糖喂养大鼠(FFR)的心脏重构,并抑制心脏内促生长信号通路,FFR 是胰岛素抵抗的动物模型。Sprague-Dawley 大鼠给予正常大鼠饲料(对照)或相同饲料加 10%果糖饮用水。在 6 周相应饮食周期的最后 2 周,对照和 FFR 植入了输送 ANG-(1-7)(100ng.kg(-1).min(-1))的渗透泵。每组动物的一个亚组(对照或 FFR)进行了假手术。我们测定了心脏重量、心肌细胞直径、间质纤维化和血管周围胶原 III 沉积以及 ERK1/2、JNK1/2 和 p38MAPK 的磷酸化程度。FFR 表现出轻度高血压,经 ANG-(1-7)治疗后显著降低。此外,FFR 在心内显示出更高的循环和局部 ANG II 水平,在慢性 ANG-(1-7)输注后仍未改变。FFR 心脏重量与体重比、心肌细胞直径以及左心室纤维化和血管周围胶原 III 沉积均增加。有趣的是,经 ANG-(1-7)治疗后,这些心脏改变得到了显著改善。最后,长期接受 ANG-(1-7)治疗的 FFR 显示 ERK1/2、JNK1/2 和 p38MAPK 的磷酸化水平显著降低。ANG-(1-7)的有益作用与心脏内Src 同源 2 含蛋白酪氨酸磷酸酶-1(SHP-1)活性的正常值相关。总之,慢性 ANG-(1-7)治疗可改善心脏肥大和纤维化,并减弱心脏内的促生长途径。这些发现表明 ANG-(1-7)在胰岛素抵抗大鼠心脏中具有重要的保护作用。