Abstract 353: Triciribine, a Selective Akt Inhibitor, Inhibits Myofibroblast Differentiation and Ameliorates Pulmonary Vascular Remodeling in Pulmonary Hypertension

Abstract

Objectives: Idiopathic pulmonary fibrosis (IPF) is an incurable, chronic and progressive disease with severely poor prognosis and often leads to pulmonary hypertension (PH). Persistent myofibroblast (MF) differentiation in response to TGFβ, marked by de novo expression of αSMA stress fibers, is the central orchestrator of tissue fibrosis and vasculopathy. Our previous studies indicated the integral role of Akt in myofibroblast differentiation and fibrosis. Here, we investigated the efficacy of Triciribine (TCBN), a selective Akt inhibitor, currently in clinical trials for cancer therapy, as a potential therapeutic option for IPF and PH. Methods: WT and Akt1 null mice, as well as those treated with TCBN were subjected to 3 week hypoxia along with normoxia control, and the lungs were used for imaging and western analysis to study the biochemical, structural and vascular changes in the lungs. Cutting edge techniques such as microfil-cast based vascular imaging, confocal imaging and analysis of extracellular matrix protein turnover was performed for the data collection and analysis. Results: Under hypoxia, WT mice exhibited robust vascular remodeling leading to thickening of the artery wall, reduction in lumen size and loss of capillaries in the lungs. This effect was significantly less in Akt1 null mice. Treatment with TCBN significantly ameliorated vascular remodeling in mice due to hypoxia, and resulted in normalization of the vasculature with increased lumen size, reduced wall thickness and increased number of capillary branches as compared to untreated controls. TCBN also affected expression of a number of different extracellular matrix proteins and matrix metalloproteases in addition to changes in the expression of contractile proteins alpha-actin, myocardin and serum response factor in the adventitial fibroblasts. Conclusions: Our results demonstrate the crucial role of Akt as an integral mediator of MF differentiation in IPF and PH. Further, TCBN could potentially be a therapeutic option for IPF and PH.