RhoA/rho kinase pathway activation in age-associated endothelial cell dysfunction and thrombosis

Abstract

The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.

Keywords: RhoA/rho kinase pathway; ageing; cardiovascular disease; endothelial dysfunction; frailty; thrombosis.

FIGURE 1

Frailty syndrome. Frailty is characterised by a significant decrease among elderly people in their biological capacity to confront the challenges of daily life. The multiple factors that can trigger the appearance of frailty include lifestyle, genetic background, environmental quality and the existence of co‐morbidities. Frailty status is an important risk factor for chronic diseases associated with old age, which themselves promote the development of frailty.

FIGURE 2

Classical RhoA/Rho kinase pathway. Different stimuli can induce RhoA activation, through guanosine exchange factors (GEF) or inhibition through GTPase‐activating protein (GAP). Activated RhoA interacts with the Rho‐binding domain (RBD) domain of Rho kinase, releasing and activating the kinase domain. Activated Rho kinase phosphorylates multiple cell targets, including LIM kinase (LMK) and myosin phosphatase target subunit 1 (MYTP1). Phosphorylated LIMK phosphorylates, and thus inactivates, cofilin, inducing actin polymerization and stabilization. Phosphorylated MYTP1 is inactivated, resulting in the stabilization of the phosphorylated and active form of myosin light chain (MLC), thus promoting actomyosin contraction and cell migration.

FIGURE 3

RhoA/Rho kinase pathway activation in age‐related vascular disease. Abnormal activation of the RhoA/Rho kinase pathway has been linked to aging and cellular senescence. Frailty syndrome, directly related with unhealthy ageing, may increase the risk of abnormal RhoA/Rho kinase activation, in turn triggering pathological cell mechanisms that lead to age‐related vascular disease and promote a prothrombotic status in elderly people. MLC, myosin light chain; OE, oxidative stress; VSMCs, vascular smooth muscle cells.