Transient angiotensin-converting enzyme inhibition confers sex-specific protection against angiotensin II-induced cardiac remodeling.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Alexandra M Garvin, Dana B Floyd, Alexis C Bailey, Merry L Lindsey, Chad C Carroll, Taben M Hale
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Abstract

Hypertension increases the prevalence of heart failure to a greater extent in women than men. The fibrotic remodeling of the left ventricle (LV) is a major contributor to increased myocardial stiffness and eventual decrease in cardiac function. Cardiac fibrosis can be prevented in the spontaneously hypertensive rat (SHR) by transient angiotensin-converting enzyme inhibitors (ACEi) in males. Whether transient ACEi also protects against fibrosis in females is not known. In the present study, we evaluated angiotensin II (Ang II)-induced cardiac fibrosis and related signaling in male and female SHR to determine how these responses are altered by prior transient ACEi treatment. Relative changes in blood pressure response to both ACEi and Ang II were similar between sexes, whereas Ang II-induced cardiac hypertrophy was attenuated by prior ACEi in males only. Ang II-induced changes in gene expression for collagens I, III, and IV were attenuated by prior ACEi in males but not females. Despite these sex-specific differences, prior ACEi-attenuated Ang II-induced increases in fibrogenic proteins [phosphorylated SMAD3/SMAD3, periostin, and lysyl oxidase (LOX)] and pro-oxidative proteins (NOX2 and NOX4), as well as hydroxyproline (HYP) content similarly in both sexes. Interestingly, a positive correlation between angiotensin II type 1 (AT1) receptor gene expression and Col1a1 in Ang II-treated males is absent in the female SHRs. The observed sex differences in the protection afforded by prior ACEi suggest altered signaling for collagen deposition that may lead to a greater understanding of the sex-dependent efficacy of antihypertensive drugs.NEW & NOTEWORTHY Here, we determine, for the first time that female spontaneously hypertensive rats are responsive to transient angiotensin-converting enzyme inhibitor (ACEi) treatment. Prior work showed that transient ACEi treatment induced persistent protection against a future stimulus in males. Here, Ang II-induced cardiac fibrosis was attenuated by transient ACEi treatment in both sexes. Notably, the underlying mechanism of action is sex-dependent. Specifically, changes in collagen deposition in male but not female hearts correlate with collagen gene expression.

短暂性血管紧张素转换酶抑制对血管紧张素ii诱导的心脏重构具有性别特异性保护作用。
高血压在女性中比在男性中更大程度地增加心力衰竭的患病率。左心室的纤维化重塑是心肌僵硬增加和最终心功能下降的主要原因。雄性瞬时血管紧张素转换酶抑制(ACEi)可预防自发性高血压大鼠(SHR)损伤性心脏纤维化。暂时ACEi是否也能防止女性纤维化尚不清楚。在本研究中,我们评估了血管紧张素II (Ang II)在男性和女性SHR中诱导的心脏纤维化和相关信号,以确定这些反应如何被先前的短暂ACEi治疗所改变。两性对ACEi和angii的血压反应的相对变化相似,而在男性中,只有先前的ACEi减轻了angii诱导的心脏肥厚。在男性中,angii诱导的胶原I、III和IV基因表达的变化被先前的ACEi所减弱,而在女性中则没有。尽管存在这些性别特异性差异,但先前的ACEi在两性中相似地减弱了Ang ii诱导的纤维原蛋白(磷酸化的SMAD3/SMAD3、骨膜蛋白和赖氨酸氧化酶)和促氧化蛋白(NOX2和NOX4)以及羟脯氨酸含量的增加。有趣的是,angii治疗的男性血管紧张素II型1受体基因表达与Col1a1之间的正相关在女性SHRs中不存在。观察到的先前ACEi提供的保护的性别差异表明胶原沉积信号的改变可能导致对抗高血压药物性别依赖性疗效的更好理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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