在高血压孕鼠中刺激 ACE2/Ang-(1-7)/Mas 轴可减轻成年雄性子代的心血管功能障碍。

Stimulation of the ACE2/Ang-(1-7)/Mas axis in hypertensive pregnant rats attenuates cardiovascular dysfunction in adult male offspring.

机构信息

Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, Goiânia, GO, 74.690-900, Brazil.

Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, 74.690-900, Brazil.

出版信息

Hypertens Res. 2019 Dec;42(12):1883-1893. doi: 10.1038/s41440-019-0321-8. Epub 2019 Sep 10.

Abstract

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.

摘要

本研究旨在探讨在自发性高血压大鼠(SHR)孕期使用二甲氮嗪(DIZE)或血管紧张素-(1-7)(Ang-(1-7))治疗是否可以减轻成年子代心血管功能障碍的发展。为此,将 DIZE 或 Ang-(1-7)给予妊娠 SHR。通过尾套测压法在雄性子代 6 至 16 周龄时测量收缩压(SBP)。之后,通过 Langendorff 技术评估左心室收缩功能和冠状动脉反应性。在另一批成年大鼠子代中,收集左心室(LV)和肾脏样本,用于组织学和 Western blot 分析。孕期给予 DIZE 或 Ang-(1-7)治疗可减轻成年子代 SBP 的升高。此外,DIZE 和 Ang-(1-7)治疗均降低了 LV 中的心肌细胞直径和纤维化沉积,而 Ang-(1-7)治疗还降低了肾脏中的纤维化沉积。DIZE 和 Ang-(1-7)治疗均改善了成年子代离体心脏中缓激肽诱导的冠状动脉扩张。然而,这些动物的 LV 收缩功能没有差异。LV 中 AT1 和 Mas 受体、ACE、ACE2、SOD 和过氧化氢酶的表达水平不受 Ang-(1-7)治疗的影响,但该治疗可降低 AT2 的表达。这些数据表明,孕期使用 DIZE 或 Ang-(1-7)治疗可促进减轻成年子代高血压和心脏重塑的有益作用。

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