The Role of the Impaired PPARs in Vascular Proliferation and Remodeling Associated with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by increased small pulmonary vascular resistance, and caused by increased migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs). For the treatment of PAH, prostacyclin and its analogs activate cell-surface prostacyclin (IP) receptors, leading to the inhibition of PASMC proliferation. However, the lungs of some patients have decreased expression of the IP receptor, and the absence of IP receptors worsens PAH. Past studies have suggested that prostacyclin analogs can also activate the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs), and the PPAR signaling pathway is crucial for the development of PAH. However, results in our laboratory have shown that patients with idiopathic PAH lack PPAR alpha, beta/delta, gamma, and a similar expression pattern was observed in MCT-induced PAH. Furthermore, several cancer studies have shown that PPAR can regulate the transcription of phosphatase and tensin homolog on chromosome ten (PTEN), a known tumor suppressor, in cancer cell proliferation and migration. Previously, our research group had demonstrated that upregulation of PTEN can inhibit vascular smooth muscle cell (VSMC) proliferation, and migration in the development of atherogenesis. All past work considered, the mechanisms underlying the suppressive effects of prostacyclin and the PPARs-PTEN signaling pathway in PAH are still not well understood. This proposal addresses the hypothesis that (a) vascular remodeling progresses through crosstalk between the PPARs and PTEN signaling pathways in controlling PASMC proliferation and migration, and (b) based on data, we develop a long half-life prostacyclin analog for treatment of PAH. This study investigates the following aims. (1) Understand if there is crosstalk between the PPARs/PPREs and PTEN/PI3K/Akt pathways in the suppressive effect of prostacyclin on PAH development. (2) Identify if PPARs are impaired in SMC of PAH, can prostacyclin, via the PPARs-PTEN signaling pathway inhibit the proliferation, migration, and dedifferentiation of PASMCs in vitro. (3) Understand if prostacyclin can suppress PAH via the PPARs-PTEN signaling pathway in monocrotaline-treated rats and PTEN mutant mice transgenic mice in vivo. (4) Determine if the development of long half-life prostacyclin suppresses PAH with severe pulmonary vascular remodeling via PPARs and PTEN induction. Execution of these studies will provide a deeper understanding of the pathogenesis of PAH. In addition, the results may help to define the role of prostacyclin/PPARs /PTEN in preventing progressive and fatal PAH, and provide new approaches for therapeutic intervention in PAH.

Project ID:PC10301-1140
External Project ID:NSC101-2314-B182-076-MY3