Signal Transducers and Activators of Transcription-3/Pim1 Axis Plays a Critical Role in the Pathogenesis of Human Pulmonary Arterial Hypertension

Abstract

Background Pulmonary artery hypertension (PAH) is a proliferative disorder associated with enhanced pulmonary artery smooth muscle cell proliferation and suppressed apoptosis. The sustainability of this phenotype required the activation of a prosurvival transcription factor like signal transducers and activators of transcription-3 (STAT3) and nuclear factor of activated T cell (NFAT). Because these factors are implicated in several physiological processes, their inhibition in PAH patients could be associated with detrimental effects. Therefore, a better understanding of the mechanism accounting for their expression/activation in PAH pulmonary artery smooth muscle cells is of great therapeutic interest. Methods and Results Using multidisciplinary and translational approaches, we demonstrated that STAT3 activation in both human and experimental models of PAH accounts for the expression of both NFATc2 and the oncoprotein kinase Pim1, which trigger NFATc2 activation. Because Pim1 expression correlates with the severity of PAH in humans and is confined to the PAH pulmonary artery smooth muscle cell, Pim1 was identified as an attractive therapeutic target for PAH. Indeed, specific Pim1 inhibition in vitro decreases pulmonary artery smooth muscle cell proliferation and promotes apoptosis, all of which are sustained by NFATc2 inhibition. In vivo, tissue-specific inhibition of Pim1 by nebulized siRNA reverses monocrotaline-induced PAH in rats, whereas Pim1 knockout mice are resistant to PAH development. Conclusion We demonstrated for the first time that inhibition of the inappropriate activation of STAT3/Pim1 axis is a novel, specific, and attractive therapeutic strategy to reverse PAH.

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

“…Furthermore, using the same time course as in Figure IC in the online-only Data Supplement, we observed that BRD4 expression within the coronary arterial wall slightly increased (not significant) within the first 2 weeks after monocrotaline injection, being significantly overexpressed 3 weeks after monocrotaline injection ( Figure IIB in the online-only Data Supplement), when PAH is already established. 5 To validate our observations in PAH animal models, we also observed a 2-fold increase in the amount of BRD4-positive cells within the coronary arterial wall Sugen/hypoxiainduced PAH ( Figure IIC in the online-only Data Supplement). To strengthen our findings, we measured BRD4 expression by Western blot in isolated human coronary artery smooth muscle cells (hCoASMCs) from patients with PAH.…”

“…The similarities in histological features between PAH and other VRDs suggest common pathogenic mechanisms. We and others have described the implication of the receptor of advanced glycation endproducts, 2-4 the oncoprotein kinase Pim-1 3,5 and the transcription factor nuclear factor of activated T cells 6,7 in promoting proliferation in remodeling processes occurring in both VRD and PAH. In PAH patients' lung vasculature, these molecular actors are, at least in part, regulated by proinflammatory cytokines, alterations in the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis [8][9][10][11] and subsequent overexpression of the epigenetic reader bromodomain protein 4 (BRD4).…”

Potassium channels in pulmonary arterial hypertension

“…2) [60]. Indeed, increased STAT3 activation has been described in normal PASMCs treated with TNF-α or interleukin-6, suggesting that the decrease in K + current elicited by these inflammatory factors is due, at least in part, to a STAT3-dependent pathway [61,62].…”

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

“…In vitro, several studies reported increased activation of NFATc2 in cultured PASMC in response to 5-HT, endothelin-1(ET-1) and PDGF, which has been implicated in pulmonary vascular remodeling. 16,17 NFATc2 induces PASMC proliferation and resistance to apoptosis within the remodeling PA wall by reducing the expression of Kv1.5 and upregulation of anti-apoptotic protein Bcl-2. 14,18 Kv1.5 has been suggested to regulate the resting plasma membrane potential in PASMC.…”