miR-21 is associated with fibrosis and right ventricular failure
Sushma Reddy, … , Giovanni Fajardo, Daniel Bernstein
Sushma Reddy, … , Giovanni Fajardo, Daniel Bernstein
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e91625. https://doi.org/10.1172/jci.insight.91625.
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Research Article Cardiology

miR-21 is associated with fibrosis and right ventricular failure

Abstract

Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement.

Authors

Sushma Reddy, Dong-Qing Hu, Mingming Zhao, Eddie Blay Jr., Nefthi Sandeep, Sang-Ging Ong, Gwanghyun Jung, Kristina B. Kooiker, Michael Coronado, Giovanni Fajardo, Daniel Bernstein

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Figure 3

miR-21 is a biomarker of RV dysfunction in mice.

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miR-21 is a biomarker of RV dysfunction in mice. (A) RV expression of pr...
(A) RV expression of profibrotic miR-21 was upregulated during the stages of diastolic (1 month and 2 months) and systolic (3 months) dysfunction compared with sham-operated controls. n = 6–8/sham and PI+PS/time point. (B) The expression of miR-21 positively correlated with the degree of RV fibrosis as diastolic dysfunction progressed, but that correlation was lost once systolic dysfunction developed. (C) miR-21 expression is upregulated in the hearts in PI+PS mice and not in the livers, spleens, or lungs. n = 5/sham; n = 8/PI+PS. (D) miR-21 is expressed predominantly in nonmyocytes. n = 4/sham; n = 6–8/PI+PS. (E) Plasma miR-21 was upregulated with diastolic dysfunction but switched to being downregulated with the development of systolic dysfunction, despite persistent tissue-level upregulation (n = 9–10/sham and PI+PS/time point); miR-21 is expressed in plasma exosomes. (F) TEM demonstrating exosomes (arrows) 50–100 nm in size, with characteristic cup shape (arrowhead) and surrounding halo. Scale bar: 500 nm (top); 200 nm (bottom). (G) Exosome marker expression was similar at all time points. n = 2/group. (H) miR-21 is enriched in exosomes in the plasma compared with the nonexosome fraction. n = 3/sham; n = 4/PI+PS. (I) Plasma miR-21 correlated with RV end-diastolic area (RVED) as diastolic dysfunction progressed and (J) switched to a negative correlation with the onset of systolic dysfunction. (K and L) A similar correlation was seen with fibrosis. RV, right ventricle; PI+PS, pulmonary insufficiency and pulmonary stenosis; TEM, transmission electron microscopy. Data are presented as mean ± SEM. An unpaired, 2-tailed Student’s t test was utilized for 2-group comparisons and ANOVA with multiple testing correction for 3 or more group comparisons. Correlation was assessed using Pearson’s correlation. *P < 0.02, ** P < 0.001.