de Boer Rudolf A, Pokharel Saraswati, Flesch Markus, van Kampen Derk A, Suurmeijer Albert J H, Boomsma Frans, van Gilst Wiek H, van Veldhuisen Dirk J, Pinto Yigal M
Thoraxcenter, Department of Cardiology, University Hospital Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.
J Mol Med (Berl). 2004 Oct;82(10):678-87. doi: 10.1007/s00109-004-0579-3. Epub 2004 Aug 20.
Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) beta1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic d P/d t, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.
血管紧张素（Ang）II是左心室（LV）重塑和心脏纤维化的关键因素。其作用至少部分是通过丝裂原活化蛋白激酶（MAPK）、转化生长因子（TGF）β1和Smad信号通路介导的。在本研究中，我们试图阐明Ang II在体内对左心室功能障碍和纤维化的相关作用是通过MAPK介导，还是通过Smad刺激介导。我们用安慰剂、1型Ang II（AT1）受体阻滞剂或 tyrphostin A46（TYR，一种表皮生长因子受体酪氨酸激酶抑制剂，可阻断细胞外信号调节激酶（ERK）活性）处理纯合REN2大鼠（7 - 11周龄）。REN2大鼠存在左心室肥厚（LVH）和左心室功能障碍，并在10至13周之间进展为心力衰竭。血压随时间恢复正常。肾素、N端心房利钠肽（N - ANP）和ERK被激活，而p38 MAPK未被激活。用AT1受体阻滞剂治疗可预防LVH和右心室肥厚，使收缩期和舒张期dP/dt以及N - ANP水平恢复正常，并减少胶原沉积。同样，TYR可减轻LVH、降低N - ANP水平并减少胶原沉积。心肌ERK激活不依赖于AT1受体信号传导，因为它不受AT1受体阻滞剂的影响。TYR消除了心肌ERK活性。Smad2激活被AT1受体阻滞剂抑制，但不受TYR影响。Ang II诱导的左心室重塑和纤维化依赖于ERK和Smad2激活。AT1受体阻滞剂和TYR均可预防这一过程，因此抑制任何一条信号通路在恢复左心室功能和结构方面同样有效。
