Song Yi Shin, M.S.

Cardiovascular disease (CVD) remains the primary causes of deaths in the United States.
Despite a number of research to prevent or cure CVD, it is still the leading cause of morbidity and mortality worldwide. Numerous studies have found that exercise is very effective for prevention of CVD, however, there are many CVD patients who are not able to exercise at high intensity and certain duration required due to their pathological conditions or physical limits. Fortunately, there are a lot of therapeutic benefits of numerous treatment options such asstatins, angiotensin converting enzyme (ACE) inhibitors, and beta blockers. On top of these therapeutic drugs, there is an increasing evidence of the novel therapeutic target in treatment of cardiovascular diseases, the rho kinase. A number of prominent roles of rho kinase have been elucidated in several pathways. It plays a pivotal role in various cellular function, vascular smooth muscle cell (VSMC) contraction, actin skeleton organization, cell adhesion, and gene expression. This article focuses on the rho kinase in CVD, specifically hypertension and its pathways.

Rho kinase regulates cell migration by promoting cellular contraction. Rho kinase
phosphorylates myosin phosphatase target subunit 1 (MYPT 1) which regulates contraction and relaxation of VSM and maintain blood pressure. The phosphorylated MYPT 1 causes myosin light chain phosphatase (MLCP) inactive, when MLCP is inhibited, myosin light chain kinase (MLCK) causes contraction. Furthermore, a rise in Ca2+ concentration causes activation of MLCK and consequent phosphorylation of MLC and smooth muscle contraction. However, MLC phosphorylation and VSM contraction can be induced in the absence of significant increases in Ca2+ entry. As mentioned earlier, Rho kinase activation phosphorylates MYPT 1, and inhibits its activity and thereby causes Ca2+ sensitization of the contractile proteins and enhances VSM contraction. Modulation of VSMC contractility via rho kinase pathway seems to be of particular importance during tonic contractions.

Hypertension is characterized by high arterial pressure resulting from increased peripheral vascular resistance that can be attributed to both enhanced contractility of VSMC and vessel wall remodelling. Increased activity of the rho kinase pathway plays an important role in the development and maintenance of hypertension. For example, previous studies have shown that rho kinases are involved in spontaneous tone development under hypertensive conditions.
To block rho kinase activity, they used Y27632, rho kinase inhibitor, to see effects on hypertension. The results showed that it significantly reduces the tone development in arteries
from hypertensive rats but has no impact on basal tone of normotensive rats.

In conclusion, the rho kinase is a novel therapeutic target in CVD, and there is a compelling
evidence for its role in various physiological conditions. Specifically, its signalling is critically
involved in skeletal muscle VSM contraction and its abnormalities may result in impaired vascular tone regulation. Therefore, targeting the rho kinase under specific cardiovascular
pathophysiological conditions will have numerous beneficial effects on vascular function.