Dynamic Changes in miR-21 Regulate Right Ventricular Dysfunction in Congenital Heart Disease-Related Pulmonary Arterial Hypertension

Abstract

Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.

Transpulmonary Expression of Exosomal microRNAs in Idiopathic and Congenital Heart Disease–Related Pulmonary Arterial Hypertension

“… 16 , 28 For example, miR‐21, miR‐130a, and miR‐143/145 are upregulated in the exosomes of patients with PAH and have been shown to promote proliferation, migration, and inflammation in pulmonary artery smooth muscle cells and endothelial cells. 23 , 29 , 30 , 31 We also observed several key miRs with high expression levels in patients with CHD‐related PAH. 30 , 31 Among them, miR‐21 was most significantly activated in HPMECs under flow‐mediated shear stress.…”

“… 30 , 31 Among them, miR‐21 was most significantly activated in HPMECs under flow‐mediated shear stress. 3 , 23 By suppressing miR‐21 expression levels, shear stress–induced apoptosis was mitigated. 23 Therefore, exosomal miRs could be biomarkers for diagnosis and prognosis of the disease and be used as therapeutic targets for developing new treatments.…”

“… 3 , 23 By suppressing miR‐21 expression levels, shear stress–induced apoptosis was mitigated. 23 Therefore, exosomal miRs could be biomarkers for diagnosis and prognosis of the disease and be used as therapeutic targets for developing new treatments. 16 , 28 Overall, exosomal miRs play a critical role in the pathogenesis of PAH, and further research is required to understand their function and potential clinical applications.…”

“…The cultured HPMECs were subjected to shear stress in a parallel‐plate flow chamber to mimic the volume‐overloaded condition in RV under pulmonary hypertension. 23 Briefly, HPMECs were seeded onto glass slides with extracellular matrix coating to form a monolayer and subsequently sandwiched to form a flow channel with a thin silicone gasket. A mixture of 5% CO 2 and 95% air was constantly supplied at 37 °C under 6 dyn/cm 2 shear stress for 3 and 6 hours.…”

Pulmonary arterial hypertension associated with congenital heart disease: An omics study

“…In addition, a previous article found that the expression of circulating miR-21 of PAH-CHD patients was higher than that of normal controls. However, patients with heart failure had significantly lower expression of circulating miR-21 and left ventricular dysfunction (47). miR-223 is a potential circulating biomarker and small molecule drug for the diagnosis and treatment of PAH.…”