Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure
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.
- SourceAvailable from: Jolyane MelocheCurrent Vascular Pharmacology 01/2013; · 2.91 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.The Canadian journal of cardiology 01/2015; 31(4). DOI:10.1016/j.cjca.2015.01.023 · 3.94 Impact Factor
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ABSTRACT: miRNAs are important regulators of gene expression through interaction with the 3'UTR of target mRNAs. The role of miRNAs has been extensively studied in adult human and animal models of heart disease. Hypoplastic left heart syndrome (HLHS) is the most common form of severe congenital heart disease and is an important cause of morbidity and mortality in infants and children. The objective of this work was to analyze the miRNA profile in HLHS patients.Journal of Cardiac Failure 10/2014; DOI:10.1016/j.cardfail.2014.09.013 · 3.07 Impact Factor