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

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 <i>Col1a1</i> 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.<b>NEW & NOTEWORTHY</b> 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.