Historical emphasis on the left ventricle (LV) has left clinicians with a lack of efficacious right ventricle (RV)-specific therapies, and classical pharmacological interventions for LV failure are often not effective when re-appropriated as interventions for RV failure. Different and still largely unknown molecular mechanisms governing the two ventricles, perhaps related to the distinct embryological origins, might at least in part explain the limited understanding of RV pathophysiology. microRNAs (miRs) are major post-transcriptional regulators and their altered expression has been implicated in several cardiovascular pathologies. We hypothesized that altered miR expression specific to the failing RV may underlie the molecular pathophysiology of progressive mechanical RV dysfunction. We applied an “-omics” approach to a pre-clinical, large animal model of heart failure. Ten dogs were subjected to 4-week tachypacing to induce congestive heart failure (HF) and secondary pulmonary hypertension. Ten non-paced dogs were used as normal controls. Hemodynamic and echocardiographic assessment confirmed development of RV dysfunction and secondary pulmonary hypertension in tachypaced dogs. In HF vs control, RV end-diastolic pressure and mean pulmonary arterial pressure were significantly increased, while tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and RV fractional area change were significantly decreased. miR microarray and quantitative RT-PCR analyses both showed upregulation of several miRs in HF-RV vs HF-LV and control myocardium. We focused on miR-21, which increased in HF-RV vs control RV (with no change in HF-LV vs control LV) and is known to target phosphatase and tensin homolog (PTEN), a negative regulator of fibroblast proliferation. PTEN also inhibits the phosphorylation/activation of Akt, a positive regulator of fibroblast proliferation. Myocardial PTEN was indeed selectively downregulated in HF-RV and not in HF-LV, consistent with increased fibrosis in HF-RV vs HF-LV. Moreover, Akt phosphorylation was increased by in RV-HF and reduced in HF-LV vs control. Isolated fibroblasts and myocytes from each ventricle were subjected to cyclic stretch and/or aldosterone treatment to mimic mechanical and hormonal stimuli occurring during HF. In RV fibroblasts, miR-21 was increased by both cyclic stretch and by aldosterone, with no significant miR-21 increase in any other cell type. Furthermore, in stretched/treated RV fibroblasts there was a significant downregulation of miR-21 targets PTEN and sprouty homolog 1, as well as a significant upregulation of pro-fibrotic mediator transforming growth factor-β1. These findings suggest that miR-21 upregulation due to RV fibroblast responsiveness to mechanical and hormonal stimuli is a novel determinant of RV fibrosis and functional impairment. This study uncovered a novel, major biological difference between the RV and LV, specifically a peculiar molecular response of RV fibroblasts to mechanical and hormonal stress. It is my hope that my findings will contribute to what will eventually lead to a clear, clinically relevant understanding of the mechanisms underlying RV failure. / Physiology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/3420 |
| Date | January 2016 |
| Creators | Powers, Jeffery |
| Contributors | Recchia, Fabio, Recchia, Fabio, Houser, Steven R., Sabri, Abdelkarim, Dries, Daniel |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 114 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/3402, Theses and Dissertations |
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