Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury

Abstract

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a,-224 and-452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R 2 0.04, R = 0.21, p = 0.001, 95% CI 0.103-0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a,-224 and-452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a,-224 and-452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF. Abbreviations MiR MicroRNA HFpEF Heart failure with preserved ejection fraction HFrEF Heart failure with a reduced ejection fraction LVDD Left ventricular diastolic dysfunction DM Diabetes mellitus X-linked X-chromosome located XIST X-inactive-specific transcript Ang-2 Angiopoietin-2 sFlt-1 Plasma soluble Flt-1 sTM Plasma soluble thrombomodulin PE Preeclampsia

Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452

“…Still, in women, we previously demonstrated increased circulating levels of miR-224/452 in contrast to no significant effects in the transmen cohort ( Fig. 1G and H ) ( 43 ).…”

Circulating miRNA as potential biomarkers for diabetes mellitus type 2: should we focus on searching for sex differences?

“…Last but not least research demonstrates that the sex-specific expression level of miRNA could be analyzed together with other markers to indicate diabetes complications. Heart failure with preserved ejection fraction (HFpEF) is an example of diabetes microvascular complications that have more prevalence in women and are frequently undiagnosed at the early stage of development (Florijn et al 2020). Interestingly, the elevated expression level of a protein marker of microvascular injury angiopoietin-2 (Ang-2) only in diabetic females with HFpEF along with lower expression levels of miR-224 and miR-452 in diabetic males with HFpEF (Florijn et al 2020) shows their potential to serve as sex-biased biomarkers.…”

“…Heart failure with preserved ejection fraction (HFpEF) is an example of diabetes microvascular complications that have more prevalence in women and are frequently undiagnosed at the early stage of development (Florijn et al 2020). Interestingly, the elevated expression level of a protein marker of microvascular injury angiopoietin-2 (Ang-2) only in diabetic females with HFpEF along with lower expression levels of miR-224 and miR-452 in diabetic males with HFpEF (Florijn et al 2020) shows their potential to serve as sex-biased biomarkers. In summary, all the mentioned results demonstrate the need for the development of sex-specific diagnostic strategies in diabetes mellitus type 2, as well as show the possibility of using circulating miRNAs as sex-biased biomarkers.…”

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

“…Previously, we reviewed the question of whether these mechanisms result in sex-specific microRNA expression within female microvascular cells [ 31 ]. We subsequently demonstrated that their sex-specific expression instigates a different clinical outcome in women compared to men, such as a higher prevalence of microvascular injury (defined by elevated angiopoietin-2 levels) following diabetes mellitus [ 32 ]. Lastly, we described the regulatory role of angiogenic microRNAs in cerebral small vessel disease [ 33 ].…”