Heart failure is the common end-stage for cardiac disease and is a problem of major public health significance. Despite longstanding research into the basic mechanisms underlying pathological remodeling and heart failure, current therapies remain inadequate, and 5-year mortality for heart failure remains at 50%. Recently, there has been increasing interest in the role of cardiac fibroblasts in ventricular remodeling, including ho cardiac fibroblasts respond to paracrine signals originating in the stressed myocyte. Understanding how cardiac fibroblasts and myocytes together contribute to remodeling resulting in heart failure should lead to new therapeutic strategies that will improve the prognosis for those with chronic cardiovascular conditions. Osteopontin (OPN) is a secreted protein that signals between cardiac myocytes and fibroblasts. OPN plays pivotal roles in the regulation of proliferation, survival, adhesion, and migration of cells by signaling through integrin and CD44 receptors. OPN expression is highly induced in heart failure. Using a constitutive, global knockout mouse, OPN has been shown to promote the interstitial myocardial fibrosis induced by pressure overload8 or myocardial infarction (MI). Similarly, by gene deletion, CD44 has been found to promote fibroblast proliferation in vivo after MI and in vitro. However, the cellular mechanisms conferring OPN-CD44 signaling in cardiac remodeling remain unknown. We have recently developed a novel method by which to block OPN function, in vivo injection of a protein-binding RNA molecule called OPN RNA aptamer. Using the OPN RNA aptamer, we have confirmed that OPN is required for pressure overload-induced left ventricular remodeling. Moreover, aptamer injection attenuated the development of heart failure. Inspired by these results, the goal of this application is to explore the cell autonomous mechanisms by which OPN contributes to interstitial fibrosis. By mass spectroscopy, we have identified novel OPN binding partners, including extracellular matrix proteins Fibronectin-1 (FN1) and Thrombopondin-1 (TSP1), CD44 receptors, and members of the PI3K/Akt/mTOR pathway. Our central hypothesis is that the binding of cardiac OPN to CD44 receptors on cardiac fibroblasts and/or myocytes is essential for ventricular remodeling. We propose that secreted OPN interacts with extracellular TSP1/FN1, binds to CD44 receptors, and activates PI3K/Akt signaling resulting in myofibroblast differentiation and myocyte hypertrophy.
The cytokine Osteopontin is elevated in cardiovascular patients and inversely related to cardiac function. The cellular mechanism and physiological properties by which osteopontin signals through its CD44 receptor in the heart remain unknown. The goal of this project is to investigate the cellular mechanism of the cardiac Osteopontin-CD44 system and its relevance to ventricular remodeling in heart failure.
| Ding, Wen; Yousefi, Keyvan; Shehadeh, Lina A (2018) Isolation, Characterization, And High Throughput Extracellular Flux Analysis of Mouse Primary Renal Tubular Epithelial Cells. J Vis Exp : |
| Ding, Wen; Shehadeh, Lina A (2017) New incriminating evidence against IGF2. Transl Cancer Res 6:S949-S952 |
