Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
Physiological Genomics (Impact Factor: 2.81). 03/2012; 44(10):562-75. DOI: 10.1152/physiolgenomics.00163.2011
Source: PubMed

ABSTRACT MicroRNAs (miRs) are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in left ventricular hypertrophy (LVH) and failure (LVF). However, there are no data on their role in right ventricular hypertrophy (RVH) and failure (RVF). This is a critical question given that the RV is uniquely at risk in patients with congenital right-sided obstructive lesions and in those with systemic RVs. We have developed a murine model of RVH and RVF using pulmonary artery constriction (PAC). miR microarray analysis of RV from PAC vs. control demonstrates altered miR expression with gene targets associated with cardiomyocyte survival and growth during hypertrophy (miR 199a-3p) and reactivation of the fetal gene program during heart failure (miR-208b). The transition from hypertrophy to heart failure is characterized by apoptosis and fibrosis (miRs-34, 21, 1). Most are similar to LVH/LVF. However, there are several key differences between RV and LV: four miRs (34a, 28, 148a, and 93) were upregulated in RVH/RVF that are downregulated or unchanged in LVH/LVF. Furthermore, there is a corresponding downregulation of their putative target genes involving cell survival, proliferation, metabolism, extracellular matrix turnover, and impaired proteosomal function. The current study demonstrates, for the first time, alterations in miRs during the process of RV remodeling and the gene regulatory pathways leading to RVH and RVF. Many of these alterations are similar to those in the afterload-stressed LV. miRs differentially regulated between the RV and LV may contribute to the RVs increased susceptibility to heart failure.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Right ventricular (RV) failure determines outcome in patients with pulmonary hypertension, congenital heart diseases and in left ventricular failure. In 2006, the Working Group on Cellular and Molecular Mechanisms of Right Heart Failure of the NIH advocated the development of preclinical models to study the pathophysiology and pathobiology of RV failure. In this review, we summarize the progress of research into the pathobiology of RV failure and potential therapeutic interventions. The picture emerging from this research is that RV adaptation to increased afterload is characterized by increased contractility, dilatation and hypertrophy. Clinical RV failure is associated with progressive diastolic deterioration and disturbed ventricular-arterial coupling in the presence of increased contractility. The pathobiology of the failing RV shows similarities with that of the LV and is marked by lack of adequate increase in capillary density leading to a hypoxic environment and oxidative stress and a metabolic switch from fatty acids to glucose utilization. However, RV failure also has characteristic features. So far, therapies aiming to specifically improve RV function have had limited success. The use of beta blockers and sildenafil may hold promise, but new therapies have to be developed. The use of recently developed animal models will aid in further understanding of the pathobiology of RV failure and development of new therapeutic strategies.
    Heart Failure Reviews 03/2015; DOI:10.1007/s10741-015-9479-6 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure is a complex pathophysiological syndrome that can occur in children from a variety of diseases, including cardiomyopathies, myocarditis, and congenital heart disease. The condition is associated with a high rate of morbidity and mortality and places a significant burden on families of affected children and to society as a whole. Current medical therapy is taken largely from the management of heart failure in adults, though clear survival benefit of these medications are lacking. Ventricular assist devices (VADs) have taken an increasingly important role in the management of advanced heart failure in children. The predominant role of these devices has been as a bridge to heart transplantation, and excellent results are currently achieved for most children with cardiomyopathies. There is an ongoing investigation to improve outcomes in high-risk populations, such as small infants and those with complex congenital heart disease, including patients with functionally univentricular hearts. Additionally, there is an active investigation and interest in expansion of VADs beyond the predominant utilization as a bridge to a heart transplant into ventricular recovery, device explant without a heart transplantation (bridge to recovery), and placement of devices without the expectation of recovery or transplantation (destination therapy).
    Korean Circulation Journal 01/2015; 45(1):1-8. DOI:10.4070/kcj.2015.45.1.1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure is characterized by the transition from an initial compensatory response to decompensation, which can be partially mimicked by transverse aortic constriction (TAC) in rodent models. Numerous signaling molecules have been shown to be part of the compensatory program, but relatively little is known about the transition to decompensation that leads to heart failure. Here, we show that TAC potently decreases the RBFox2 protein in the mouse heart, and cardiac ablation of this critical splicing regulator generates many phenotypes resembling those associated with decompensation in the failing heart. Global analysis reveals that RBFox2 regulates splicing of many genes implicated in heart function and disease. A subset of these genes undergoes developmental regulation during postnatal heart remodeling, which is reversed in TAC-treated and RBFox2 knockout mice. These findings suggest that RBFox2 may be a critical stress sensor during pressure overload-induced heart failure. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.