Noncardiomyocyte microRNAs Mediate Dysregulation of Angiogenesis in RV Failure
Abstract
Background: This proposal is a major revision of an application that was reviewed last year for the Peer Reviewed Medical Research Program Topic Area "Congenital Heart Disease (CHD)." Our proposal was rated highly for significance and relevance, but several methods concerns were raised, especially our focus on four microRNAs (miRs), which was felt to be overly ambitious for a 3-year project. In this revision, we address all of the reviewers concerns and narrow our focus to the failure of the stressed right ventricle (RV) to generate new blood vessels (angiogenesis). We provide extensive new data supporting our hypothesis and demonstrating our ability to perform the proposed studies. Most importantly, we demonstrate the feasibility of our anti-miR approach, showing that we can successfully knockdown miR-34a in the heart, which restores angiogenesis and delays the onset of RV failure. Children or adults with CHD are at risk of RV failure (RVF). For many of these patients, detrimental conditions for the RV exist throughout life, even after successful surgery. As techniques for repair of complex congenital heart lesions continue to improve, long-term survival and quality of life will depend on our ability to preserve long-term RV function. However, most of the knowledge we have about the mechanisms underlying heart failure comes from studies of left ventricular (LV) failure, and thus most drugs used to treat heart failure derive from these studies. New research suggests that there are important differences at the cellular and molecular level between the two ventricles, highlighted by the fact that commonly used "LV" heart failure therapies are ineffective in patients with CHD with RV failure. Rationale: There are several key differences in how the RV and LV respond to stress. When the LV is stressed, one of its initial responses is to increase blood flow to muscle cells (cardiomyocytes) through the production of new capillaries (angiogenesis); this is caused by the activation of a protein, Hif-1alpha, which then activates another protein, VEGF, which induces new blood vessels to form. Only when the LV begins to fail does capillary number decrease. In contrast, in the RV, although Hif-1alpha is activated, there is a puzzling decrease in VEGF, and capillary density declines even during the early phase. This failure to maintain adequate blood flow could predispose the RV to earlier failure. The mechanisms for this dysregulation of angiogenesis are still unknown. A newly described group of molecules, known as microRNAs (miRs), have been shown to act as regulators of cellular changes during LV failure; however, there is minimal data on their role in the RV. We have described four RV-specific miRs that are increased during RV stress but not during LV stress. Two of these, miRs 34a and 148a, have been implicated in regulating angiogenesis in other cell types, but their role in the heart has not been previously determined. Unlike many miRs produced in LV failure, these two are produced in non-muscle heart cells known as endothelial cells (a component of blood vessels), and fibroblasts (support cells). This suggests that they alter angiogenesis by acting either directly on endothelial cells or indirectly on muscle cells through unique cell-cell communication (crosstalk). Our new data show that endothelial cell-produced miR-34a suppresses the production of VEGF in heart muscle cells and also increases the senescence (aging) of endothelial cells. When we inhibit miR-34a using an antimiR (a compound that blocks the function of a specific miR), angiogenesis in the stressed RV is restored to normal, and the onset of RV failure is delayed. Hypothesis: RV-specific miRs 34a and 148a, in part through direct effects in endothelial cells and in part through crosstalk with heart muscle cells, are responsible for decreased blood vessel formation in the stressed RV. Suppressing miR 34a and/or 148a expression will restor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610727
Entities
People
- Daniel Bernstein
Organizations
- Stanford University
- United States Army