PH caused by increased pulmonary blood flow is the most common complication of CHD with left-to-right shunt. The severity of PH directly affects the surgical effect and prognosis of patients [8]. At present, there is no complete explanation of the mechanism of occurrence and regulation of PH in CHD, butit has been suggested that PH is caused by many factors, such as the proliferation of pulmonary vascular smooth muscle cells, the increase of extracellular matrix components, the myostratification of non-muscular arteries, the swelling and hypertrophy of endothelial cells, and, finally, the thickening of the pulmonary artery wall and stenosis of the lumen of the pulmonary artery [9].
The role of the Rho-kinase signaling pathway in the pathogenesis of PH has drawn increasing attention in recent years [10, 11]. In particular, Fasudil, a selective inhibitor of the Rho kinase signaling pathway, has been shown to significantly inhibit the progress of pulmonary vasoconstriction and pulmonary vascular structural reconstruction in experimental animals with PH. Thus, it is postulated that the abnormal activation of Rho kinase plays an important role in the pathogenesis of PH by directly affecting the contraction of smooth muscle cells, changing the balance between endothelium-derived relaxing factors and contraction factors, and regulating the expression of cell growth genes and other mechanisms [12]. Recent studies have shown that Rho kinase can be activated by a variety of upstream stimulation signals [4, 5, 12], including ET-1, NO, angiotensin II (AngII), and oxidative stress. While previous studies have shown that all of these stimulating factors can cause PH and structural remodeling, ET-1 is by the far the strongest vasoconstrictor and a powerful mitogenic agent of smooth muscle cells. An increase in ET-1 can not only strongly contract the pulmonary artery but also promote the proliferation of vascular smooth muscle and fibrous tissue, increase pulmonary vascular resistance, and participate in the reconstruction of pulmonary vessels [12, 13]. NO can also play an important role: As an endothelium-derived relaxing factor, NO can selectively relax the pulmonary artery, inhibit the adhesion and aggregation of platelets, and reduce pulmonary artery pressure [5, 10, 14].
The present study investigated the differences in serum levels of Rho kinase, ET-1, and NO in pediatric patients with CHD accompanied by PH. The serum levels of Rho kinase, ET-1, and NO in pediatric patients with CHD accompanied by PH were compared to those of healthy children with normal pulmonary artery pressure. It was found that the levels of Rho kinase and ET-1 were significantly higher in pediatric patients with CHD than they were in the healthy control group (P< 0.01), and the serum levels of patients in the mild PAH and moderate to severe PAH groups were also significantly higher than those of patients in the non-PAH and control groups (P < 0.01). The serum level of NO in pediatric patients with CHD was significantly lower than in the healthy control group (P< 0.01), and the serum level of NO in the mild PAH and moderate to severe PAH groups was significantly lower than in the non-PAH and healthy control groups (P < 0.01). The serum levels of Rho kinase and ET-1 were significantly and positively correlated with PASP (r = 0.707 and 0.888, respectively; P< 0.01 in both), while the level of NO was negatively correlated with PASP (r = –0.696, P < 0.01). There was also a significantly negative correlation between the serum levels of Rho kinase and ET-1 and the serum level of NO (r = –0.522, –0.592, respectively; P < 0.01 in both). These results suggest that Rho kinase may play an important role in the pathogenesis of PH in pedriatric patients with CHD. As important active mediators in the regulation of vascular tension, ET-1 and NO may be involved in the formation of PH; this conclusion is consistent with relevant reports [11-14].
In conclusion, serum expression levels of Rho kinase were higher in pediatric patients with left-to-right shunt CHD and were positively correlated with PASP. The expression of serum Rho kinase was even higher in patients with PH. Thus, our results suggest that Rho kinase may interact with ET-1 and NO and participate in the occurrence and development of PH in pediatric patients with CHD. It is, therefore, of great clinical importance to measure the levels of Rho kinase, ET-1, and NO in pediatric patients with CHD, since these measurements can be used as a reference index to determine the degree of PH, and may provide a theoretical basis for the targeted treatment of children with left-to-right shunt CHD accompanied by PH.