Rho/Rho Kinase Signaling Pathway and Disease: from Bed to Bench

Abstract

Since Madaule and Axel first discovered Rho gene in 1985, Rho and its signal transduction pathway have been extensively studied. Rho protein family belongs to the small GTP binding protein of Ras super-family, whose molecular weight is between 20kd-30kd. As a molecular switch, Rho protein family controls many signal transduction pathways in eukaryotic cells. There are two states of Rho protein, one is the inactivation state bound to GDP (GDP Rho), the other is the activation state bound to GTP (GTP Rho). In the resting state, the GDP Rho dissociation inhibitor (rho GDI) is bound to the GDP Rho and located in the cytoplasm. GTP was substituted for GDP to activate Rho protein by guanosine exchange factor (GEFs). GTP Rho interacts with the downstream effector Rho kinase (ROCK). There are two types of ROCK: ROCK1 and ROCK2. The activation of ROCK can inhibit the activity of myosin phosphorylated light chain phosphatase (MYPT1), thus increasing the level of myosin phosphorylated light chain (MLC) in cells, leading to increased sensitivity of vascular smooth muscle cells to Ca2+ and vasoconstriction. Previous studies have shown that Rho/ROCK signaling pathway not only plays an important role in vasoconstriction, but also regulates cell movement, proliferation, adhesion, activation of cytokines and migration of inflammatory cells. At the molecular level, the expression of ROCK up regulates various factors that promote oxidative stress, inflammation, thrombosis and fibrosis, and down-regulates endothelial nitric oxide synthetase. At the cellular level, it is involved in many cell functions such as gene expression, cytokinesis, cell adhesion and migration. It has been found that Rho/Rho kinase is related to cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, heart failure and so on. Fasudil, a potent and selective inhibitor of ROCK, can treat many cardiovascular diseases and has been used in clinical practice. This article reviews the relationship between Rho/Rho kinase and many system diseases.