Abstract 12548: Expression of Let-7 Family microRNAs in Skin Correlates Negatively With Severity of Pulmonary Hypertension in Patients With Systemic Scleroderma

Abstract

Introduction: Pulmonary hypertension (PH) is a serious complication in patients with systemic scleroderma (SSc), therefore it is important to identify the factors that could predict the presence and progression of PH. Skin biopsy is performed in patients with SSc to examine the type and severity of the disease. MicroRNAs (miRNAs) are potential biomarkers for various cardiovascular diseases including PH. Hypothesis: In patents with systemic scleroderma (SSc), skin miRNAs expression profiles varies depending on the presence or absence of PH. Methods and Results: We determined the skin miRNA expression profile in 15 female SSc patients with (n=6) and without PH (n=9). Plasma BNP level was significantly higher in the PH group than non-PH group, but left ventricular function and dimension were not different between the two groups. A mixture of equal amounts of miRNAs from PH and non-PH patients were prepared and used for miRNA PCR array analysis. The analysis identified 591 upregulated miRNAs and 57 downregulated miRNAs in the PH group. Of these, only miRNAs with a Ct value of less than 35 were subjected to further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated and 14 miRNAs were downregulated in the PH group. Interestingly, 5 out of 14 downregulated miRNAs belonged to the let-7 family. The results were validated by quantitative real-time PCR with specific primer for each miRNA, which showed significant downregulation of five let-7 family members (let-7a, -7d, -7e, -7f, -7g) in 6 PH compared with 9 non-PH skin samples. Circulating these miRNA levels were trended to decrease in PH group, but it did not reach statistically significant. The expression of let-7b and -7d correlated significantly and negatively with the estimated pulmonary arterial pressure. The expression of let-7a, -7e, -7g, -7f tended to correlate negatively with the estimated pulmonary arterial pressure, albeit insignificantly. Conclusions: The expression level of let-7 family microRNAs in skin are lower in patients with SSc with PH than those without PH. Skin miRNA is a potentially useful marker for evaluation of PH in patients with SSc. Skin biopsy can be considered in patients with collagen diseases to identify the presence and severity of PH.