Abstract
Smooth muscle in the pulmonary artery of PAH subjects, both idiopathic and hereditary, is characterized by hyperplasia. Smooth muscle cells (HPASMC) isolated from subjects with or without PAH retain their in vivo phenotype as illustrated by their expression of alpha-smooth muscle actin and expression of H-caldesmon. Both non PAH and PAH HPASMC display a lengthy, approximately 94h, cell cycle. The HPASMC from both idiopathic and hereditary PAH display an abnormal proliferation characterized by continued growth under non-proliferative, non-growth stimulated conditions. This effector independent proliferation is JNK and p38 MAP kinase dependent. Blocking the activation of either abrogates the HPASMC growth. HPASMC from non PAH donors under quiescent conditions display negligible proliferation but divide upon exposure to growth factors such as PDGF-BB or FGF2 but not EGF. This growth does not involve the MAP kinases. Instead it routes via the tyrosine kinase receptor through mTOR and then 6SK. In the PAH cells PDGF-BB and FGF2 augment the dysregulated cell proliferation, also through mTOR/6SK. Additionally, blocking the activation of mTOR also modulates the MAP kinase promoted dysregulated growth. These results highlight key alterations in the growth of HPASMC from subjects with PAH which contribute to the etiology of the disease and can clearly be targeted at various regulatory points for future therapies.
Highlights
Pulmonary arterial hypertension (PAH) is a devastating disease of the pulmonary vasculature which is fatal and presently with limited treatment
The results indicated that the levels of activated ERK, JNK and p38 MAPK were markedly higher in both iPAH and hPAH cells compared to non PAHs (Fig 4A)
Smooth muscle cells from human pulmonary arteries in primary cultures are being utilized as a model for the smooth muscle behavior in PAH
Summary
Pulmonary arterial hypertension (PAH) is a devastating disease of the pulmonary vasculature which is fatal and presently with limited treatment. Hyperplastic Growth of PAH SMC pulmonary vascular resistance and increased pulmonary arterial pressure [2] This hypertrophy has not been brought under control therapeutically. Studies on human pulmonary artery smooth muscle cells (HPASMC) from PAH patients have described increased PAH HPASMC growth in response to stimuli such as TGFβ, BMPs [3] and serotonin [4]. These stimuli were shown to enact their growth responses through MAP kinases [5,6,7]. To move toward more effective therapy, a much better understanding of the signal cascade(s) involved in the dysregulated proliferation of PAH HPASMC has to be developed such that more specific brakes on the proliferation of these cells can be achieved
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