Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells

Abstract

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. We evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. These effects were paralleled by a progressive increase in cGMP content, followed by an accumulation of cAMP. The treatment with 8-bromo-cGMP or dibutyryl-cAMP mimicked all the effects of sildenafil. On the other hand, treatment of PASMC with inhibitors of cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) reversed the antiproliferative effect of sildenafil. In addition, sildenafil inhibited the phosphorylation of ERK, a converging point for several pathways leading to cell proliferation. This effect was partially reduced by PKG inhibition and completely abolished by PKA inhibition.We conclude that sildenafil exerts an antiproliferative effect on human PASMC that is mediated by an interaction between the cGMP-PKG and the cAMP-PKA activated pathways, leading to inhibition of PDGF-mediated activation of the ERK.

Combination Therapy With Fasudil and Sildenafil Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats

“…In contrast, sildenafil inhibits VSMC proliferation through activating the cGMP/PKG pathway, where cGMP activates PKG to induce the mitogen-activated protein kinase phosphatase-1 (MKP-1) enzyme that deactivates ERK1/2. 60, 61 In the present study, we were able to demonstrate that sildenafil reduced ERK1/2 activity in both the PA trunk and lung. Taken together, the combination therapy with fasudil and sildenafil significantly inhibits ERK1/2 activity and Rho-kinase activity compared with each monotherapy (Figure 7).…”

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

“…[7][8][9]15 Sildenafil has been shown to be beneficial in pulmonary hypertension and cardiac hypertrophy. 22,23,12 Tadalafil and sildenafil have also been shown to improve endothelial dysfunction in patients with high cardiovascular risk, chronic heart failure, diabetes and in smokers. 11,[24][25][26] There is evidence that PDE5 inhibitors may have cardioprotective effects.…”

Sildenafil Inhibits Human Pulmonary Artery Smooth Muscle Cell Proliferation by Decreasing Capacitative Ca2+ Entry

“…The relaxant effect of sildenafil appears mainly related to action on calcium signaling via the IP3-dependent calcium release pathway and calcium reuptake mechanisms (7,8). However, the mechanism of its antiproliferative effect in PASMCs has not been studied.…”