Pro-proliferative and inflammatory signaling converge on the FoxO1 transcription factor in pulmonary hypertension – a new therapeutic approach

Savai, Rajkumar; Al-Tamari, HM; Sedding, Daniel; Kojonazarov, Baktybek; Muecke, Christian; Teske, Rebecca; Capecchi,; Weißmann, Norbert; Grimminger, F.; Seeger, W.; Schermuly, RT; Pullamsetti, SS

doi:10.1055/s-0035-1544772

Cited by 1 publication

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“…The smooth muscle cell phenotype of these cells was confirmed via immunostaining for alpha smooth muscle actin [6,81]. All cell strains in this study and other published studies (not used directly here) have consistently shown that PAH HPASMC exhibit sizably increased proliferation, survival and anti-apoptosis in culture akin to their behavior in vivo [2][3][4]6,10,12,13,19,20,22,[82][83][84][85]. Specific information about the cell donors used in this study is shown in Table 1.…”

Section: Cell Culturesupporting

confidence: 63%

CDC2 Is an Important Driver of Vascular Smooth Muscle Cell Proliferation via FOXM1 and PLK1 in Pulmonary Arterial Hypertension

Pal-Ghosh¹,

Xue²,

Warburton³

et al. 2021

Preprint

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A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein we identify cyclin dependent kinase 1 (CDK1) also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7 and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in a potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.

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