Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Abstract

R ight ventricular (RV) function is a major determinant of functional capacity and survival in pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension.1 Although afterload is a prominent determinant for RV systolic function in PAH, there remains significant variability between patients with PAH in the ability of the RV to adapt to pressure overload and pulmonary resistance.2,3 The mechanisms accounting for this variability in RV adaptability to increased pulmonary load and for the transition to RV failure remain elusive. Despite the tremendous attention that left ventricular (LV) failure has received, RV failure has remained understudied at both the preclinical and clinical levels. 3 As a result, RV failure has emerged as an important research priority in the cardiopulmonary research field. Clinical Perspective on p 943Magnetic resonance imaging performed in patients with PAH has shown that the hypertrophied RV is ischemic 5 andBackground-Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results-We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31 + immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions-RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. Key Words: hypertension, pulmonary ◼ microRNAs ◼ microvessels ◼ pulmonary heart disease ◼ right ventricular failure © 2015 American Heart Assoc...

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

“…Similarly, Potus and colleagues [45] discover that miR-126-3p can improve right heart function in patients with pulmonary hypertension through the Ras/extracellular signal-regulated kinase (ERK)/VEGF pathway by targeting Spred1. underlying mechanism might be that miR-126-3p upregulation increases right heart microvessel density.…”

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

“…A recent study showed that patients with CAD have lower circulating levels of miR-126, likely playing a role in plaque instability. 47 In PAH, miR-126 was also described as an important player of endothelial integrity and its downregulation in patients with PAH led to decreased vascular density in the RV 33 and peripheral muscle. 32 Thus, these epigenetic alterations may also increase the susceptibility of patients with PAH to develop CAD.…”

“…This concept is not surprising because PAH is now recognized not to be restricted to the lungs. [31][32][33][34] Therefore, we hypothesize that sustained activation of BRD4 during PAH will progressively contribute to coronary alterations (CAD or MVD) in these vulnerable patients. This may be attributable to detrimental conditions, such as increased inflammation, known to cause DNA damage and activate this epigenetic reader, 15,17,35 that propagate to the coronary arteries and activate the BRD4 axis in the heart.…”

MicroRNA in cardiovascular biology and disease

“…Administration of miR-126 mimics ameliorates microvascular density, improves RV function and diminishes fibrosis, whereas antagomiR-mediated miR-126 downregulation exacerbates RV failure. 39 Recent research by Halkein et al proposed the 16-kDa N-terminal fragment of the nursing hormone prolactin (16K PRL) as a potential factor initiating and driving peripartum cardiomyopathy (PPCM). Expression of miR-146a is induced in endothelial cells (ECs) by 16K PRL.…”