Decreased circulating levels of the lipid-regulating miR-122 are associated with prior preeclampsia in women with premature acute coronary syndrome

BACKGROUND: Pre-eclampsia is a hypertensive disorder that affects 2-8% of all pregnancies, and therefore has significant implications for the cardiovascular health of an estimated 300 million women worldwide. While epidemiologic studies have identified a strong positive association between pre-eclampsia and the development of cardiovascular disease, the molecular determinants underlying this association remain poorly understood. However, there is increasing interest in the role of microRNAs (miRNAs), which have been shown to exert pervasive regulatory actions in cardiovascular biology. OBJECTIVE: To identify miRNAs that circulate at different levels in women diagnosed with premature acute coronary syndrome (ACS), with and without a prior history of preeclampsia (PE) or gestational hypertension (GH). METHODS: Total RNA was extracted from archived plasma samples from a derivation cohort of three groups of women with a diagnosis of premature ACS and a prior history of either pre-eclampsia, gestational hypertension, or normotensive pregnancy (NP) (n=11-13 subjects/group). The groups were closely matched on potential confounding variables including age, chronic hypertension, diabetes, smoking status and type of ACS. A total of 372 different miRNAs were measured by high-density PCR-array (Qiagen), and normalized using a mean-centering restricted method. Alterations in candidate miRNA levels were further validated in a larger cohort of female premature ACS patients (n=30 PE, 37 GH, 148 NP), and corrected for technical variations using an external spike-in control. Measurements were performed blinded to the exposure status. RESULTS: In the derivation cohort, circulating levels of 16 miRNAs were significantly (p<0.05) altered in the PE versus NP groups (from -2.8 fold down to +2.0 fold up), and 32 miRNAs were significantly altered between the GH and NP groups (from -2.8 to +2.7 fold change). These miRNAs showed little to no overlap with previously published reports of circulating miRNAs that were altered acutely at the time of preeclamptic pregnancy or ACS event. One miRNA, miR-122-5p, was concordantly decreased in both the PE and GH groups versus NP controls, and was robustly detectable in circulation. The circulating levels of miR-122-5p were also significantly (p<0.05) reduced in the larger validation cohort of PE subjects versus NP controls. CONCLUSION: An unbiased assessment of circulating miRNAs revealed decreased levels of the lipid-regulator, miR-122-5p, in female ACS patients with a history of pre-eclampsia. This study identifies a novel molecular link that may help to explain the association between pregnancy-associated hypertension and increased risk of future cardiovascular disease.