Fasudil Hydrochloride Hydrate, a Rho-Kinase Inhibitor, Suppresses 5-Hydroxytryptamine-Induced Pulmonary Artery Smooth Muscle Cell Proliferation via JNK and ERK1/2 Pathway

Abstract

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary artery hypertension, and inhibition of PASMC proliferation has been shown to be beneficial to patients with this disease. Recent studies indicate that Rho/ROCK is critically involved in the proliferation of smooth muscle cells. However, the signal transduction of Rho/ROCK and its downstream signaling are not fully understood. In the present study, we investigated the antiproliferation effect of fasudil hydrochloride hydrate, a Rho-kinase inhibitor, on rat PASMC proliferation, and the possible relation of Rho/ROCK to ERK, JNK pathways. The results indicate that fasudil effectively inhibited 5-HT-induced PASMC proliferation, as evaluated by MTT assay and protein expression of proliferating cell nuclear antigen. Flow cytometry analysis showed that fasudil markedly blocked 5-HT-induced cell-cycle progression by arresting the cells in the G₀/G₁ phase. Consistently, 5-HT-induced ROCK-1 mRNA expression and MYPT-1 phosphorylation were markedly suppressed by fasudil. In addition, fasudil significantly decreased 5-HT-induced JNK activation, ERK translocation to the nucleus and subsequent c-fos and c-jun expression. Taken together, these results indicate that Rho/ROCK is essential for PASMC proliferation produced by 5-HT. Fasudil effectively suppressed 5-HT-induced PASMC proliferation and cell-cycle progression, which was associated with inhibition of JNK activation, ERK translocation to nucleus and subsequent c-fos and c-jun expression.

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

“…58 Fasudil inhibits VSMC proliferation by blocking the nuclear translocation of ERK1/2. 59 All of these reports support our present study finding that treatment with fasudil inhibited the phosphorylation of Rho-kinase and ERK1/2. 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.…”

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

“…This seems to be because of a side-effect of the inhibitor in the epidermis, namely the concomitant inhibition of Rok signaling and ERK phosphorylation ( Supplementary Fig. S8B), sporadically observed in other tissues (25)(26)(27). ERK inhibition by Fasudil is not observed in the forestomach (Fig.…”

High glucose induces Rho/ROCK-dependent visfatin and type�I procollagen expression�in�rat primary�cardiac fibroblasts

“…It has been suggested that ROCK1 plays a key role in pathological fibrosis of the organs, whereas ROCK2 is related to organ hypertrophy (23,24). Other studies found that ROCK not only increases the polymerization of the actin cytoskeleton, but also induces the expression of fibrosis-related genes and proteins (19,23,25,26). Phrommintikul et al (23) confirmed in the animal model of stress-induced cardiac hypertrophy that the ROCK inhibitor reduces the synthesis of cardiac collagen, and improves the diastolic function.…”