Sugen 5416 followed by chronic hypoxia significantly increased right ventricular miR-155 expression by 9.5-fold at day 14 (p=0.0006), which strongly correlated with metrics of RV remodeling.
RCT
Randomized
In a rat model of pulmonary hypertension, miR-155 expression is elevated in the right ventricle and strongly correlates with endostatin levels and maladaptive right ventricular remodeling, identifying it as a potential therapeutic target.
Effect estimate: 9.5-fold increase
p-value: p=0.0006
Abstract Rationale Endostatin (ES), a fragment of collagen XVIII (COL18A1), is a prognostic biomarker in pulmonary arterial hypertension (PAH) associated with adverse hemodynamics and increased mortality. However, the molecular mediators of its effects remain incompletely defined. Previous studies have demonstrated that ES induces the expression of microRNA-155 (miR-155) in cancer cells. Consistently, our preliminary data demonstrates ES robustly upregulates miR-155 expression. miR-155 has been linked to endothelial cell dysfunction and identified as a key regulator of gene expression in these cells. Additionally, miR-155 expression promotes cardiac hypertrophy and dysfunction in pressure overload and myocarditis models. Despite these associations with pathological remodeling in left heart disease, its role in right ventricular (RV) dysfunction and PAH has not been explored. We hypothesized that miR-155 is an ES-dependent mediator contributing to maladaptive RV remodeling in PAH. Methods Male Wistar rats were randomized to receive a single dose of Sugen 5416 followed by chronic hypoxia (SuHx) or vehicle treatment in room air for 7, 14, or 21 days. Hemodynamics, RV morphology, and mRNA/microRNA expression were analyzed in RV, left ventricle (LV), and lung tissue over time. Spearman correlation analyses assessed relationships between miR-155, COL18A1, and metrics of RV remodeling and afterload. Results In the SuHx rat model, RV miR-155 expression was significantly increased by 9.5-fold at day 14 (9.5 ± 7.8, p = 0.0006) and 6.2-fold at day 21 (6.2 ± 0.4, p =0.03) versus controls, with no significant changes on day 7. LV miR-155 expression increased 5.3-fold at day 21 (5.3 ± 2.0, p 0.0001). In lungs, miR-155 levels rose 2.2 ± 0.01 (p 0.0001) on day 7, 1.3 ± 0.3 (p = 0.02) on day 14, and 2.0 ± 0.1 (p 0.0001) on day 21. RV miR-155 expression correlated strongly with COL18A1 mRNA (ρ = 0.8, p = 0.02) and metrics of RV remodeling including RV weight (ρ = 0.9, p 0.01), RV/body weight ratio (ρ = 0.9, p = 0.002), and Fulton’s index (ρ = 0.9, p = 0.01), but not with RV systolic pressure. Conclusions In the SuHx PAH model, miR-155 expression was elevated in the heart and lungs, with the most robust increase in the RV. RV miR-155 expression is strongly associated with COL18A1 levels and metrics of RV remodeling. These findings identify miR-155 as a potential ES-dependent mediator of maladaptive RV remodeling and a novel therapeutic target in PAH. This abstract is funded by: NIH HL114910/R01 (PMH) and NIH HL132153/R01(RLD/PMH)
Ambade et al. (Fri,) conducted a rct in Pulmonary arterial hypertension. Sugen 5416 followed by chronic hypoxia (SuHx) vs. Vehicle treatment in room air was evaluated on Right ventricular miR-155 expression at day 14 (9.5-fold increase, p=0.0006). Sugen 5416 followed by chronic hypoxia significantly increased right ventricular miR-155 expression by 9.5-fold at day 14 (p=0.0006), which strongly correlated with metrics of RV remodeling.
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