Pulmonary arterial hypertension (PH) is a fatal disease with uncontrolled pulmonary vascular cell proliferation. Excessive endothelial cell (EC) growth leads to the formation of plexiform lesions, which are a characteristic cancer-like change within pulmonary arteries of patients with PH. The increased oxidative stress in lungs of patients with PH leads to the reaction of superoxide with NO. This results in the formation of highly reactive peroxynitrite (ONOO-) which, in turn, can produce nitro-tyrosine modifications in proteins. Lung tissues from patients with PH have an increased level of protein nitration. Our recently published work indicates that the nitration of tyrosine 350 residue in Akt leads to the sustained activation of Akt signaling. The activation of Akt is a well described cell survival and stress response but Akt activation is tightly regulated by the regulatory kinases/phosphatases (PTEN, PI3K, PDK1 and mTOR) that control Akt activity and ensuring that it is only temporarily active. Pathological activation of the Akt pathway has been implicated in various cancers. We hypothesize that in PH, nitration of Akt increases translocation of eNOS to mitochondria, which downregulates oxidative phosphorylation and activates Pyruvate Carboxylase (PC), which upregulates anaplerosis. This activation of anaplerosis then leads to pathological hyper-proliferation of endothelial cells (EC) and plexiform lesion formation in PH. Further, we propose to target pathological Akt signaling using an Akt- binding peptide conjugated with an antioxidant (shielding peptide) that only affects nitration mediated Akt activation. We will test these hypotheses in the following Aims:
AIM 1 : To elucidate the role of nitration (Y350) mediated Akt activation in activation of anaplerosis in EC.
AIM 2 : To determine whether inhibition of Akt nitration disrupts formation of the apoptosis resistant and proliferative EC phenotype.
AIM 3 : To examine the effect of Akt shielding peptide on EC hyper-proliferation in the SU5416/hypoxia PH models.
Pulmonary arterial hypertension (PH) is a progressive condition, characterized by a continued increase in pulmonary circulatory pressure due to uncontrolled pulmonary vascular cell proliferation that ultimately leads to right heart failure and death. Excessive endothelial cell (EC) growth leads to the formation of plexiform lesions, which are a characteristic cancer-like change within pulmonary arteries of patients with PH. There is no cure and limited therapeutic options. We have developed a novel shielding peptide approach to stop uncontrolled EC proliferation by inhibition of pathological Akt signaling.
|Rafikov, Ruslan; Sun, Xutong; Rafikova, Olga et al. (2015) Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells. Redox Biol 6:278-86|