Article

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: 2.37). 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.

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    • "Interactive CardioVascular and Thoracic Surgery (2015) 1–6 ORIGINAL ARTICLE – ADULT CARDIAC doi:10.1093/icvts/ivv303 Interactive CardioVascular and Thoracic Surgery Advance Access published November 10, 2015 date [5] "
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    ABSTRACT: Objectives: Outcomes of tricuspid valve replacement are poor, partly due to right heart remodelling. The research on its underlying mechanisms is hampered by a lack of animal models of tricuspid regurgitation (TR). Our objective was to create a reproducible and clinically compatible TR animal model to study right heart remodelling caused by TR. Methods: Fourteen juvenile male Beagle dogs were divided randomly into an intervention group (n = 11) and a sham-operated control group (n = 3). The intervention group underwent thoracotomy and right atrial incision following superior and inferior vena caval occlusion. The anterior leaflet, together with the chordae, of the tricuspid valve was resected in eight dogs ('one leaflet' group), whereas both anterior and posterior leaflets, together with the chordae, were resected in three dogs ('two leaflets' group). The right atrium and chest were then closed. The control group underwent the same procedure, except leaflet resection. One dog from the 'two leaflets' group and one control dog were sacrificed and autopsy was performed at 12 months post-surgery. Results: All dogs survived over the 1-year observation period postoperatively. TR grade IV occurred immediately postoperatively in the 'one leaflet' group, and TR grade IV plus in the 'two leaflets' group. The overall procedure lasted 30-40 min, and the mean time of vena caval occlusion was 87 ± 10 s. Central venous pressure increased from 6 ± 1.2 at baseline to 13 ± 1.7 mmHg (P < 0.01). By 12 months after TR creation, both in the 'one leaflet' group and in the 'two leaflets' group, the right atrial area, tricuspid annular diameter and right ventricular index of myocardial performance increased significantly, right ventricular fractional area change and tricuspid annular plane systolic excursion decreased significantly. Autopsy of the intervention dog revealed oedema, ascites and cirrhosis. Conclusions: Our surgical technique to create a TR animal model was reproducible with high success and survival rates. This animal model would prove suitable to investigate the mechanisms of right heart remodelling.
    Preview · Article · Nov 2015 · Interactive Cardiovascular and Thoracic Surgery
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    • "Mice with severe PS developed edema, decreased RV function, followed by high mortality. In their study, Reddy and colleagues evaluated mice with severe PS at three time points after surgery: early hypertrophy (2 days), late hypertrophy (4 days), and heart failure (10 days) [103]. They demonstrated that the transition from RVH to RVF might be characterized by the expression of miR-34 (upregulated in 10 days PAC only), miR-21 (upregulated in 4 days following PAC and less upregulated in 10 days post-PAC), and miR-1 (downregulated in 4 days PAC and less down in RVF) [98]. "
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    ABSTRACT: MicroRNAs have emerged as key players of gene regulation during development and disease states like cancer and cardiovascular diseases. Pulmonary arterial hypertension (PAH), a vascular disease characterized by pulmonary resistance vessel occlusion is not spared by microRNA implication. This is not surprising since PAH shares common aberrantly activated pathways with cancers that lead to proliferation and survival of pulmonary arterial smooth muscle cells, among others, within the artery wall and narrowing the lumen. Recent studies demonstrated the role of miR-204 and miR-206 in pulmonary artery smooth muscle cell (PASMC) proliferation. Other microRNAs, such as miR-145, miR-21 and the miR17/92 cluster, have been associated with the disrupted BMPR2 pathway. During the last couple of years, the number of studies on the role of microRNA in PAH has broadened, defining it clearly as a HOT TOPIC. This current review presents an overview of the most recent knowledge as well as future possibilities. The use of microRNA therapies is still uncertain and poorly applied in the clinical setting yet. It is still critical to increase the knowledge and the translational potential of this HOT TOPIC to make it become a HOPE TOPIC.
    Full-text · Article · May 2013 · Current Vascular Pharmacology
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    • "Mice with severe PS developed edema, decreased RV function, followed by high mortality. In their study, Reddy and colleagues evaluated mice with severe PS at three time points after surgery: early hypertrophy (2 days), late hypertrophy (4 days), and heart failure (10 days) [103]. They demonstrated that the transition from RVH to RVF might be characterized by the expression of miR-34 (upregulated in 10 days PAC only), miR-21 (upregulated in 4 days following PAC and less upregulated in 10 days post-PAC), and miR-1 (downregulated in 4 days PAC and less down in RVF) [98]. "

    Full-text · Article · Jan 2013 · Current Vascular Pharmacology
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