McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al

McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. mice,[47] and hypoxia increases expression in mouse PA endothelial cells. In an interesting intersection with metabolic therapies for PAH, mice overexpressing the serotonin transporter benefit by treatment with the pyruvate dehydrogenase kinase (PDK) inhibitor, dicholoroacetate.[48] gene-modified endothelial progenitor cells (EPCs) have been shown to incorporate into the lung tissue and attenuate MCT-induced PH in rats.[57] Aerosolized ADM appears not to cause systemic vasodilatation.[58] are ligand-activated transcription factors that belong to the nuclear receptor superfamily. On ligand activation, PPARs heterodimerize with the retinoid X receptor and bind to PPAR response elements in regulatory promoter regions of their target genes. A series of recent observations suggests that PPAR could be a drug target in PAH.[124,125] PPAR is a downstream target of bone morphogenetic protein 2 (BMP2) in human PASMCs.[125] PPAR is important for BMP2-mediated inhibition of PDGF-induced vascular SMC proliferation.[124] Mice lacking SMC PPAR develop PAH.[124] PPAR activation stimulates apolipoprotein E expression. Recombinant apolipoprotein E inhibits PDGFR-Cmediated SMC GW-870086 proliferation and migration.[126] PPAR targets, impartial of apolipoprotein E, may Edn1 also be important in the suppression of pulmonary vascular remodeling, because male apolipoprotein EC/ mice fed a high-fat diet develop PAH that is reversed by rosiglitazone, a PPAR agonist.[125] PPAR agonists have direct anti-inflammatory and proapoptotic effects. The iPAH patients have reduced lung expression of PPAR and apolipoprotein E mRNA. Because the thiazolidinedione rosiglitazone is usually widely used in the treatment of type II diabetes mellitus, a trial in PAH would be feasible. Despite this promise, rosiglitazone failed to ameliorate PH in hypoxic-PH rats, although it did reduce right ventricular hypertrophy (RVH) and pulmonary vascular remodeling.[127] is GW-870086 expressed in PASMCs and is activated by chronic hypoxia in a calcineurin-dependent manner.[136] In these experiments, it was shown that chronic hypoxia-induced RV hypertrophy, upregulation of -SM-actin and vascular remodeling were mediated by calcineurin/in lung and PASMCs. Inhibition of nuclear factor of activated T-cells (NFAT) signaling by either VIVIT or cyclosporine restored KV1.5 expression, leading to decreased proliferation and increased apoptosis.[137] In vivo, cyclosporine treatment reversed established MCT-induced PAH. Additionally, levels were increased in circulating leukocytes from PAH patients versus healthy volunteers. CD3 + lymphocytes with activated were GW-870086 seen in the arterial wall in PAH but not in normal lungs. It should be noted that many cytokines/chemokines known to be upregulated in PAH [interleukin (IL)-6, tumor necrosis factor (TNF) , regulated and normal T-cell expressed and secreted (RANTES) and fractalkine] are regulated by NFAT. Thus, targeting NFAT signaling in PH may lead to a reduction in inflammatory, remodeling and RV hypertrophic responses. Other approaches may include direct antibody targeting of chemokine/cytokine receptors such as CCR5, CCR2 and CXCR4. IL-6 is usually emerging as a potential target in PAH, although it is not clear whether increased IL-6 expression is usually causative, or a reflection of the underlying inflammation. Higher levels of IL-6 are found in chronic obstructive pulmonary disease (COPD) patients with PH. Mice overexpressing IL-6 in the lung develop spontaneous GW-870086 PH.[138] In addition, there is an association of PAH with Castleman’s disease in man, known to be associated with high circulating levels of GW-870086 IL-6.[139] Case reports of tocilizumab,[140] a humanized antihuman IL-6 receptor monoclonal antibody in connective tissue disease associated PAH, have shown benefit. has been used successfully in certain cancers and vascular diseases including restenosis of systemic vessels and lymphangio leiomyomatosis.[146] Rapamycin is usually a well-known immunosuppressive agent with antiproliferative activity, not only against lymphocytes, monocytes and EPCs, but also against resident vascular cells.[147] Rapamycin binds to the FK-binding protein 12 and this complex binds to the mammalian targets of rapamycin (mTOR) leading to inhibition of both DNA and protein synthesis and cell.