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Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17β-estradiol (E₂) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of <i>IL-1α</i>, <i>IL-6</i>, <i>Mmp9</i>, <i>Mmp12</i>, <i>Col1α1</i>, and <i>Col3α1</i> was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with <i>Col1α1</i> and <i>Col3α1</i> expression 1-week post-surgery (r = −0.79 <i>p</i> < 0.001; r = −0.6 <i>p</i> = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while <i>Col1α1</i>, <i>Col3α1</i>, <i>IL-1α</i>, <i>IL-6</i>, <i>Tnfα</i>, <i>Mmp12</i>, and <i>FasL</i> gene expression was significantly lower in E₂- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with <i>Col3α1</i> in T12/OVX/ E₂ (r = −0.56 <i>p</i> = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E₂ replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.