Sex-Specific Regulation of Local Gonadal Hormone Signaling During Pathological Cardiac Remodeling in Spontaneously Hypertensive Rats

Abstract

Hypertensive heart disease is characterized by cardiac fibrosis in the left ventricle (LV). Angiotensin II (Ang II) promotes cardiac fibrosis through direct actions on cardiac fibroblasts. Gonadal hormones are known to impact cardiac fibrosis either through direct actions on fibroblasts or through modulation of Ang II receptors. We have previously shown that Ang II infusion alters collagen gene expression in a sex-specific manner. The present study seeks to further understand our observed sex difference by investigating the impact of Ang II on gonadal hormone regulation in the left ventricle (LV) and cardiac fibroblasts (CFs) following a fibrogenic stimulus. For whole LV analysis, male and female SHR (15-week-old) were infused with Ang II (400ng/kg/min, s.c.) or vehicle for 2 weeks via an osmotic mini pump (n=8-11 per group per sex). For CF-specific analysis, primary CFs were isolated from adult male and female SHR LV and cultured on CytoSoft cell culture plates (8 kPa stiffness) coated with Type I Collagen. CFs were brought to P1 for expansion and treated with TGFb1 (10ug/uL) or vehicle (PBS + 0.1% BSA) for 48 hours (n=7-8 per group per sex). Col1a1, AT1aR, estrogen receptors α and β (ER-α, ER-β), androgen receptor (AR), 5α-reductase (5α-R), and aromatase gene expression in the left ventricle was assessed via RT-qPCR and data analyzed by Two-Way ANOVA. Ang II infusion significantly increased ER-α gene expression in male, but not female LV (sex x Ang II interaction p=0.0303). ER-β gene expression was also significantly increased in the male LV (p=0.0066), but not females. AR gene expression remained unchanged in the Ang II-infused male LV but was significantly reduced in female LV when compared to control (sex x Ang II interaction p=0.0084). Ang II significantly increased 5α-R gene expression in male (p=0.0024), but not female LV. Aromatase gene expression tended to increase in both male and female Ang II-infused animals when compared to control. Ang II-induced changes in LV gonadal hormone gene expression did not significantly correlate with Col1a1 gene expression. In vitro stimulation of CFs with TGFb1 results in a significant reduction in ER-α (p<0.0001) and AR (p<0.0001) in both males and females. ER-β tended to decrease in males stimulated with TGFb1, but not females, relative to control. Taken together, the opposing findings between LV and CF may indicate cell-specific regulation of gonadal hormone receptors. It may be that upregulation of local estrogen signaling in the remodeling LV in males serves to offset the pathological effects of Ang II stimulation. Future studies will evaluate the consequences of changes in gonadal hormone receptor levels at the cellular and tissue level. NHLBI R01HL153112. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.