Participation of PLK1 and FOXM1 in the hyperplastic proliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension

Abstract

Vascular smooth muscle cells from the pulmonary arteries (HPASMC) of subjects with pulmonary arterial hypertension (PAH) exhibit hyperplastic growth. The PAH HPASMC display an increased sensitivity to fetal bovine serum (FBS) and undergo growth at a very low, 0.2%, FBS concentration. On the other hand, normal HPASMC (obtained from non-PAH donors) do not proliferate at low FBS (0.2%). A previous genomic study suggested that the nuclear factor, FOXM1 and the polo like kinase 1 (PLK1) are involved in promoting this hyperplastic growth of the PAH HPASMC. Here we find that limiting the action of FOXM1 or PLK1 not only restricts the hyperplastic proliferation of the PAH HPASMC but also modulates the FBS stimulated growth of normal HPASMC. The PAH HPASMC exhibit significantly elevated PLK1 and FOXM1 expression and decreased p27 (quiescence protein) levels compared to normal HPASMC. Regulation of the expression of FOXM1 and PLK1 is accompanied by the regulation of downstream expression of cell cycle components, Aurora B, cyclin B1 and cyclin D1. Expression of these cell cycle components is reversed by the knockdown of FOXM1 or PLK1 expression/activity. Furthermore, the knockdown of PLK1 expression lowers the protein level of FOXM1. On the other hand, inhibiting the action of FOXO1, a growth inhibitor, further increases the expression of FOXM1 in PAH HPASMC. Although PLK1 and FOXM1 clearly participate in PAH HPASMC hyperplasia, at this time it is not clear whether their increased activity is the primary driver of the hyperplastic behavior of the PAH HPASMC or merely a component of the pathway(s) leading to this response.

Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension

“…These data further support the finding that Egln1 Tie2Cre lung PVECs are pro-proliferative. Previous studies from multiple groups have demonstrated that FoxM1, a key transcriptional factor for cell cycle progression, is upregulated in PASMCs and contributes to the hyperproliferation of PASMCs and vascular remodeling of PAH [ 9 , 14 , 15 , 16 ]. As pulmonary ECs from PAH patients share similar pro-proliferative features with PAMSCs, therefore we further examined FoxM1 expression in the lung sections from IPAH patients via immunohistochemistry staining.…”

Endothelial Autocrine Signaling Contributes to Severe Pulmonary Arterial Hypertension

“…These data further support the finding that Egln1 Tie2Cre lung PVECs is hyperproliferative. Previous studies from multiple groups have demonstrated that FoxM1, a key transcriptional factor for cell cycle progression, is upregulated in PASMCs and contributes to the hyperproliferation of PASMCs and vascular remodeling of PAH [7,[12][13][14]. As pulmonary ECs from PAH patients share similar hyperproliferative features with PAMSCs, therefore we further examined FoxM1 expression in the lung sections from IPAH patients via immunohistochemistry staining.…”

“…Proliferation specific transcription factor FoxM1 has been shown to regulate EC, SMC, fibroblast proliferation in the disease model of acute lung injury [9,20], pulmonary hypertension [7,[12][13][14] and interstitial lung fibrosis [9], respectively. In our previous studies, we first checked the expression of FoxM1 in cultured PAEC from IPAH patients and healthy donors, but we did not observe a significant change of FoxM1 protein expression [7].…”

Therapeutic Potential of Regorafenib—A Multikinase Inhibitor in Pulmonary Hypertension

“…It is highly expressed in various tumors including breast, colorectal, kidney, prostate, non-small cell lung carcinoma, KRAS-induced lung cancer, and targeting AurB kinases displayed inhibition of cancer progression [ 58 , 59 , 60 , 61 , 62 ]. Furthermore, inhibition of growth factors like forkhead box M1 (FOXM1) and polo-like kinase 1 (PLK1) in PAH-PASMCs displayed a significant reduction of cell cycle component AurB [ 63 ], suggesting that targeting AurB kinase might have beneficial effects in treating PH. Inhibition of protein kinase N1 (PKN1) has shown anti-proliferative and anti-migratory effects in aortic vascular smooth muscle cells and vascular remodeling in the carotid artery balloon injury (BI) model [ 64 ].…”