Garvin Alexandra M, Floyd Dana B, Bailey Alexis C, Lindsey Merry L, Carroll Chad C, Hale Taben M
Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, United States.
Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States.
Am J Physiol Cell Physiol. 2025 Apr 1;328(4):C1303-C1317. doi: 10.1152/ajpcell.00753.2024. Epub 2025 Mar 7.
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 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. 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.
高血压在女性中比男性更易引发心力衰竭。左心室（LV）的纤维化重塑是心肌僵硬度增加及最终心功能下降的主要原因。在雄性自发性高血压大鼠（SHR）中，通过短暂使用血管紧张素转换酶抑制剂（ACEi）可预防心脏纤维化。短暂使用ACEi对雌性是否也有抗纤维化作用尚不清楚。在本研究中，我们评估了雄性和雌性SHR中血管紧张素II（Ang II）诱导的心脏纤维化及相关信号传导，以确定这些反应如何因先前短暂的ACEi治疗而改变。两性对ACEi和Ang II的血压反应相对变化相似，而Ang II诱导的心脏肥大仅在雄性中被先前的ACEi减弱。Ang II诱导的I、III和IV型胶原蛋白基因表达变化在雄性中被先前的ACEi减弱，但在雌性中未减弱。尽管存在这些性别特异性差异，但先前的ACEi同样减弱了Ang II诱导的促纤维化蛋白[磷酸化SMAD3/SMAD3、骨膜蛋白和赖氨酰氧化酶（LOX）]和促氧化蛋白（NOX2和NOX4）的增加，以及两性中的羟脯氨酸（HYP）含量。有趣的是，在雌性SHR中，血管紧张素II 1型（AT1）受体基因表达与Ang II处理的雄性中不存在正相关。先前ACEi提供的保护中观察到的性别差异表明胶原蛋白沉积的信号传导改变，这可能有助于更深入了解抗高血压药物的性别依赖性疗效。在此，我们首次确定雌性自发性高血压大鼠对短暂血管紧张素转换酶抑制剂（ACEi）治疗有反应。先前的研究表明，短暂的ACEi治疗可诱导雄性对未来刺激产生持续保护。在此，短暂的ACEi治疗减弱了两性中Ang II诱导的心脏纤维化。值得注意的是，潜在的作用机制是性别依赖性的。具体而言，雄性而非雌性心脏中胶原蛋白沉积的变化与胶原蛋白基因表达相关。
