Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

Abstract

Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 microm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 +/- 1.6 vs. 32.9 +/- 7.5 mmHg). Arterial oxygen tension was lower (92.3 +/- 12.5 vs. 66.0 +/- 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 +/- 3.8 vs. 36.5 +/- 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase alpha expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 +/- 3.7, 17.1 +/- 3.2, 14.3 +/- 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 +/- 16.2, 94.9 +/- 23.0, 89.1 +/- 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

Effect of simvastatin on the SIRT2/NF-κB pathway in rats with acute pulmonary embolism

“… 2006 ; Toba et al. 2010 ). However, the blood flow was restricted by the thrombus with the increase of pulmonary vascular resistance and mPAP, as well as the elevation of RVSP and ultimately leading to right ventricular failure or even death (Gutte 2011 ).…”

“…As reported, there was about 8% of pulmonary embolism (PE) patients who are diagnosed and treated in time, while untreated PE related to a mortality number ∼30% (Toba et al. 2010 ). Generally, the pulmonary artery hypertension (PAH) induced by the sharp rise of pulmonary vascular resistance can lead to the rapid increase of pressure load on the right ventricle (RV), thus causing acute right ventricular failure and circulatory shock, which is the major cause of death by APE (Venkatesh 2011 ; Cau et al.…”

Preferential Vasodilator Effects of Levosimendan in Resistance Pulmonary Arteries in a Rodent Pulmonary Embolism Model

“…One explanation would be that vascular dysfunction is observed in vivo and once PA rings are isolated their response in vitro to the diverse stimulus was similar to vessels from sham animals. Another explanation would be related with the lower time spent to the PE-induced PH on other PE models (from 180 min to several hours) [27,28]. Anyway, if the activation of the inflammatory response with the release of vasoactive mediators and increase of oxidative stress play some role in the pathogenesis of PH associated with PE [21,29], levosimendan would also have the advantage of attenuating the PE-induced PH through mechanisms involving antioxidant effects [30,31].…”

RhoGTPase in Vascular Disease

“…Several studies have shown a direct relationship between venous endothelial function and cardiovascular events, such as pulmonary embolism, venous thromboembolism, and venous insufficiency [54]. Risk factors for these events include older age, smoking, obesity, diabetes, atherosclerosis, and pulmonary disease [55,56]. Rho kinase pathway modulates endothelial fibrinolytic activity by up-regulating thrombogenic molecules like platelet-activating factor plasminogen activator inhibitor-1 [57] and tissue factor [58] and fibrogenic molecules like transforming growth factor-β1 (TGFβ1) [59].…”