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

Abstract

microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics 44: 562-575, 2012. First published March 27, 2012 doi:10.1152/physiolgenomics.00163.2011 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. heart failure; right ventricle CARDIAC REMODELING IN RESPONSE to stress results from activation and repression of genes encoding proteins that regulate cardiac contractility and structure. As novel mechanisms of remodeling are uncovered to understand the basic mechanisms of disease, an additional layer of regulation mediated by stress-responsive microRNAs (miRs) has emerged. miRs are small, noncoding RNAs of 18 -25 nucleotides that regulate gene expression by degradation or translational suppression of mRNA. miRs have retained sequence conservation across species, indicating a strong evolutionary role in fundamental biologic processes. Since the discovery of the first miR in 1993, their role in cell differentiation, proliferation, apoptosis, and stress responses has been elucidated. Their role in cardiovascular development, left ventricular hypertrophy (LVH), and heart failure is only now being understood. (8, 13).Van Rooij et al. (56) elucidated the miR expression profile in LVH in a model of thoracic aortic constriction. Many of the induced and repressed miRs were regulated in the same direction in fetal, hypertrophic, and failing human hearts, consistent with the known reactivation of the fetal gene program with st...

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

“…A total of 93 miRs were found to be differentially regulated in HLHS hearts, which clustered separately compared to NF hearts. In a mouse model, some of these miRs have been implicated in the fetal program during heart failure (miR-208) (35) and in RV hypertrophy and RV failure (miR-30, miR-378) (36). Additionally, three miR species (miR-99a, miR-100, miR-145a) were down-regulated prior to or directly after the stage 1 operation of the Norwood procedure while the values returned to control levels after the stage 3 operation (34).…”

“…HLHS is one of the most challenging CHDs, resulting in problems including RV failure and insufficient growth of pulmonary vasculature (121 Figure 2) have been implicated to regulate the pathophysiological development of the RV (36). Accumulating evidence indicates a role for miR-378 in the regulation of angiogenesis which may in turn influence the impairment of vasculature in these patients (37).…”

“…In vivo overexpression of miR-208 stimulated fibrosis (99) and enhanced CH. Additionally, this miR is implicated to regulate heart failure in mice (36).…”

Stem and Progenitor Cell Therapy for Pulmonary Arterial Hypertension: Effects on the Right Ventricle (2013 Grover Conference Series)

“…A new player in this field is the family of microRNAs of which the expressions are changing during the process of RV remodeling. 17 MicroRNAs are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in LVH and LV failure. 18,19 …”

MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine

“…A subset of miRNAs which are up-and downregulated in experimental heart failure [31] are also modulated in failing human hearts [31, [103][104][105][106]. A number of miRNAs have been shown to be either upregulated (miR-21, miR-29b, miR-129, miR-210, miR-211, miR-212, miR-423, miR-199 family, miR-379, miR-503, and miR34b and c) or downregulated (miR-30, miR-182, and miR-526) [106,107]. Consistent with the reexpression of the fetal gene program, a high degree of similarity was found between the miRNA expression patterns occurring in human failing hearts and those observed in human fetal hearts, thus indicating that a fetal miRNA program is also reactivated by cardiac stress [106].…”