Role of Akt-Myocardin-Serum Response Factor Signaling Axis in Myofibroblast Transformation and Pulmonary Hypertension

Project: Research


  • Maha Abdalla (PI)


Pulmonary arterial hypertension (PAH) is a progressive and incurable lung disease that is associated with poor prognosis for which therapeutic options are limited by the high susceptibility to drug resistance. Therefore, identification of novel therapeutic targets is critical in the hopes of devising new treatments. The hallmark of PAH is progressive vascular hypertrophy and remodeling, characterized by the accumulation of differentiated myofibroblasts (MFs); MFs differentiate from fibroblasts and express alpha-smooth muscle-like actin (aSMA) stress fibers and excess extracellular matrix (ECM) secretions. We have previously shown that Akt, a major survival protein, is necessary for transforming growth factor beta (TGFb)-induced synthesis of ECM proteins. However, the role of Akt in regulating aSMA synthesis and vascular occlusion remains unknown. Intriguing preliminary data showed that Akt null mice were protected from vascular remodeling compared to WT mice in response to chronic hypoxia (a model of PAH). These effects were associated with marked decrease in aSMA levels and its transcriptional activators myocardin- serum response factor (SRF) in vivo. In vitro sustained hyperactivation of Akt resulted in ~7-fold increase in aSMA expression in mouse embryonic fibroblasts (MEFs). Treatment with triciribine (TCBN), a selective inhibitor of Akt activation, blunted aSMA and SRF expressions, as well as its transcription co-activator myocardin, in TGFb-stimulated MEFs and human lung fibroblasts (HLFs). Thus, I propose two specific aims to test the central hypothesis that sustained activation of Akt mediates TGFb-induced MF differentiation via increasing myocardin-SRF expression leading to aSMA synthesis and resulting in vascular remodeling in PAH. Aim 1, I will test that Akt mediates MF differentiation via myocardin-SRF, using MEFs and HLFs. Aim 2, I will determine that Akt is integral for hypoxia-induced vascular remodeling in PAH in vivo using WT, Akt null mice, and WT-TCBN treated mice. I will test the central hypothesis using a combined approach of pharmacological, genetics, and state of the art molecular research tools. Successful completion of these aims will 1) identify Akt as a novel and a major regulator of fibrogenic switch in MF differentiation and vascular remodeling in PAH, and 2) determine the protective effects of triciribine, an anti-cancer drug, at a therapeutic dose 20 times lower than that used in cancer therapy.
Award amount$52,000.00
Award date07/01/2013
Program typePredoctoral Fellowship
Award ID13PRE17100070
Effective start/end date07/01/201308/01/2014