Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis
Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis
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DOI：
10.1161/01.hyp.0000111831.50834.93
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发表时间：
2004-02
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影响因子：
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通讯作者：
K. Tokuda;H. Kai;F. Kuwahara;H. Yasukawa;N. Tahara;Hiroshi Kudo;Kiyoko Takemiya;M. Koga;Tomoka Yamamoto;T. Imaizumi
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作者：
K. Tokuda;H. Kai;F. Kuwahara;H. Yasukawa;N. Tahara;Hiroshi Kudo;Kiyoko Takemiya;M. Koga;Tomoka Yamamoto;T. Imaizumi
摘要血管紧张素II（Ang II）与多种疾病的促炎过程有关。因此，我们试图确定血管紧张素II在压力超负荷（PO）心脏的早期炎症诱导的纤维化中的作用。在第0天，雄性Wistar大鼠通过肾上主动脉缩窄（AC）诱导PO，并从第-7天开始每天经口给予0.1 mg/kg坎地沙坦。这是在AC高血压大鼠（AC大鼠）中不改变动脉压的坎地沙坦最大剂量。在AC大鼠中，心脏血管紧张素转换酶（ACE）活性在第1天后短暂增强，在第3天达到峰值，在第14天下降到较低水平，而血清ACE活性没有变化。在AC大鼠中，PO诱导早期纤维炎性变化（单核细胞趋化因子[MCP]-1和TGF]-表达、血管周围巨噬细胞蓄积和成纤维细胞增殖），此后，左心室肥大发展，以肌细胞肥大、心肌内动脉壁增厚、血管周围和间质纤维化为特征。坎地沙坦抑制MCP-1和TGF-β的诱导，并减少PO心脏中的巨噬细胞积聚和成纤维细胞增殖。坎地沙坦显著预防血管周围和间质纤维化。然而，坎地沙坦不影响心肌细胞肥大和动脉壁增厚。总之，亚降压剂量的坎地沙坦可预防PO心脏中MCP-1介导的炎症过程和反应性心肌纤维化。血管紧张素Ⅱ可能在高血压心脏的反应性纤维化中起关键作用，与动脉压变化无关。
Abstract—Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day −7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]- expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF- and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1–mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.