Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY/ABSTRACT Failure of the right ventricle (RV) is a main component of the morbidity and mortality of pulmonary hypertension (PH). There exists no specific treatment for RV dysfunction and failure and the only cure for many patients (especially in the case of pulmonary arterial hypertension) remains transplantation. This is partially due to the critical lack of understanding of RV biology; therapeutic strategies that are beneficial for LV failure have worse outcomes when applied to those with RV failure. What has been observed in RV dysfunction in human subjects and animal models is exaggerated fibrosis and divergent contractile and hypertrophic responses to several drugs when compared to LV dysfunction. Thus, the RV may contain distinct pathobiology compared to the LV that has high significance for treatment of PH. A greater understanding of RV cellular biology is needed to develop new opportunities toward our long-term goal of discovering tailored therapies for dysfunction and failure of the RV. We performed transcriptomic analysis to compare the RV with the LV using Sprague Dawley rats and found significant differences in immune-related and fibrotic genes. Flow cytometry was used to confirm that the RV of control rats had an average of four-fold higher density of immune cells, namely macrophages/monocytes, compared to the LV. When rats were subject to pressure overload via hypoxia in combination with the VEGF pathway inhibitor Sugen, the RV became hyper-fibrotic. This was also clear in isolated fibroblasts from the RV of control rats, which had a higher proliferation rate and an alteration of metabolic genes. Thus, we were led to our central hypothesis: the RV is primed for disproportionate dysfunction under pressure overload due to the unique physiology of its cellular constituents, namely immune cells and fibroblasts. We will investigate this hypothesis with the following two aims: Aim 1: Determine the role of the immune response in the RV during adaptive and adverse remodeling. We will test the hypothesis that distinctive macrophage populations in the RV are critical for the “hyper-fibrosis” found in RV disease, and modulating specific inflammatory signals will be able to dampen the fibrotic response. Aim 2: Identify the fibrotic mediators in RV fibroblasts in situ and in vitro. We will test the hypothesis that RV fibroblasts have altered cellular metabolic programming that causes an enhanced fibrotic response, mediated by interactions with cardiac macrophages. This project will provide new understanding of the cellular processes that occur during pathologic remodeling of the RV. This knowledge is expected to yield new therapeutic approaches for RV dysfunction and failure occurring with PH, which currently have no specific treatment.
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