Atrial natriuretic peptide inhibits angiotensin II-stimulated proliferation in fetal cardiomyocytes
Atrial natriuretic peptide inhibits angiotensin II-stimulated proliferation in fetal cardiomyocytes
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DOI：
10.1113/jphysiol.2010.191098
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发表时间：
2010-08-01
影响因子：
5.5
通讯作者：
Thornburg, K. L.
中科院分区：
文献类型：
--
作者：
O'Tierney, P. F.;Chattergoon, N. N.;Thornburg, K. L.
心房利钠肽（ANP）在调节胎儿心脏生长中的作用尚不清楚。当生长依赖于丝裂原活化蛋白激酶（MAPK）和磷酸肌醇-3激酶（PI3K）途径的活性时，血管紧张素II （Ang II）刺激胎羊心肌细胞的增殖。我们假设ANP会抑制体外近期胎儿心肌细胞增殖，并抑制MAPK和PI3K通路。在含或不含ANP （0.003-100 nm）或1 μ m 8-溴- cgmp的100 nm Ang II中，从胎羊（135天胎龄）分离的心肌细胞对48小时5-溴脱氧尿苷（BrdU）的摄取（用作增殖指标）进行了测量。在用Ang II、ANP或8-溴- cgmp处理10分钟后，通过测量细胞外信号调节激酶（ERK）和AKT磷酸化来评估这些化合物对MAPK和PI3K通路的影响。在右心室肌细胞（RV）中，最低剂量的ANP （0.003 nm）抑制Ang ii刺激的BrdU摄取68%。同样，8-溴- cgmp抑制Ang ii刺激的增殖62%。左心室（LV）心肌细胞也有同样的作用，但左心室对ANP的抑制作用比左心室更敏感（P < 0.0001）。100 nm ANP使细胞内cGMP增加4倍。100nm ANP抑制Ang ii刺激的ERK和Akt磷酸化。ANP的活性可能部分依赖于cGMP，因为8-溴-cGMP对心肌细胞有类似的作用。
The role of atrial natriuretic peptide (ANP) in regulating fetal cardiac growth is poorly understood. Angiotensin II (Ang II) stimulates proliferation in fetal sheep cardiomyocytes when growth is dependent on the activity of the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3K) pathways. We hypothesized that ANP would suppress near-term fetal cardiomyocyte proliferation in vitro and inhibit both the MAPK and PI3K pathways. Forty-eight hour 5-bromodeoxyuridine (BrdU) uptake (used as an index of proliferation) was measured in cardiomyocytes isolated from fetal sheep (135 day gestational age) in response to 100 nm Ang II with or without ANP (0.003-100 nm) or 1 mu m 8-bromo-cGMP. The effects of these compounds on the MAPK and PI3K pathways were assessed by measuring extracellular signal-regulated kinase (ERK) and AKT phosphorylation following 10 min of treatment with Ang II, ANP or 8-bromo-cGMP. In right ventricular myocytes (RV), the lowest dose of ANP (0.003 nm) inhibited Ang II-stimulated BrdU uptake by 68%. Similarly, 8-bromo-cGMP suppressed Ang II-stimulated proliferation by 62%. The same effects were observed in left ventricular (LV) cardiomyoytes but the RV was more sensitive to the inhibitory effects of ANP than the LV (P < 0.0001). Intracellular cGMP was increased by 4-fold in the presence of 100 nm ANP. Ang II-stimulated ERK and Akt phosphorylation was inhibited by 100 nm ANP. The activity of ANP may in part be cGMP dependent, as 8-bromo-cGMP had similar effects on the cardiomyocytes.