The development of cardiac hypertrophy is mediated, in part, by increase in NADPH oxidase activity and myocardial oxidative stress. The Rho GTPase, Rac, regulates NADPH oxidase activity through interaction with gp91^phoxand p67^phox(in which “phox” is phagocyte oxidase). However, it is not known which Rac isoform mediates this effect in the heart. Here we show that Rac1 is critical for generating oxidative stress and producing cardiac hypertrophy in the adult heart. The Rac1 gene was temporally and specifically deleted in adult mouse cardiomyocytes (c-Rac1^−/−). Compared with wild-type or Rac1 heterozygous mice, the hearts of c-Rac1^−/−mice showed decreased gp91^phoxand p67^phoxinteraction, NADPH oxidase activity, and myocardial oxidative stress in response to angiotensin II (400 ng/kg per day for 2 weeks) stimulation. This result correlated with decreased myocardial hypertrophy. These results indicate that Rac1 is critical for the hypertrophic response in the heart and suggest that therapies which target myocardial Rac1 may be beneficial in the treatment of cardiac hypertrophy.

Increased oxidative stress impairs endothelial function and is thought to mediate vascular disease. Several pathological conditions increase the production of reactive oxygen species (ROS) in the vascular wall, including hypercholesterolemia, diabetes, and hypertension. These conditions are associated with endothelial dysfunction and cardiovascular disease. Thus, overall vascular function is dependent upon the balance of oxidant and antioxidant mechanisms, which determines endothelial function. Endothelial function is usually defined as nitric oxide (NO) production and/or bioavailability. Because ROS can interact and inactivate NO, vascular oxidative stress can lead to decrease NO bioavailability. This results in endothelial dysfunction and increased risk of cardiovascular diseases. Several pharmacological approaches have been used to improve endothelial function and decrease oxidative stress. These include treatment modalities that augment the antioxidant defense mechanisms, increase NO production, and inhibit ROS-generating enzymes. This review provides an overview of the relationship between endothelial function and oxidative stress.

Tight junctions (TJs) and adherens junctions (AJs) are major junctional apparatuses in epithelial cells. Claudins and junctional adhesion molecules (JAMs) are major cell adhesion molecules (CAMs) at TJs, whereas cadherins and nectins are major CAMs at AJs. Claudins and JAMs are associated with ZO proteins, whereas cadherins are associated with β- and α-catenins, and nectins are associated with afadin. We previously showed that nectins first form cell-cell adhesions where the cadherin-catenin complex is recruited to form AJs, followed by the recruitment of the JAM-ZO and claudin-ZO complexes to the apical side of AJs to form TJs. It is not fully understood how TJ components are recruited to the apical side of AJs. We studied the roles of afadin and ZO-1 in the formation of TJs in Madin-Darby canine kidney (MDCK) cells. Before the formation of TJs, ZO-1 interacted with afadin through the two proline-rich regions of afadin and the SH3 domain of ZO-1. During and after the formation of TJs, ZO-1 dissociated from afadin and associated with JAM-A. Knockdown of afadin impaired the formation of both AJs and TJs in MDCK cells, whereas knockdown of ZO-1 impaired the formation of TJs, but not AJs. Re-expression of full-length afadin restored the formation of both AJs and TJs in afadin-knockdown MDCK cells, whereas re-expression of afadin-ΔPR1–2, which is incapable of binding to ZO-1, restored the formation of AJs, but not TJs. These results indicate that the transient interaction of afadin with ZO-1 is necessary for the formation of TJs in MDCK cells.

Nectin‐like molecule‐5 (Necl‐5) is an immunoglobulin (Ig)‐like molecule that is up‐regulated in many types of cancer cells. It was shown experimentally that Necl‐5 enhances cell migration, proliferation, and metastasis, but its clinical significance has not been documented. The aim of this study was to observe the expression of Necl‐5 in surgically resected primary lung adenocarcinomas and to investigate its clinical significance. A total of 63 surgically resected primary pulmonary adenocarcinoma tissues were investigated by immunohistochemistry for the expression of Necl‐5. The relationship between expression of Necl‐5 and clinicopathological features was analyzed, and the influence of Necl‐5 expression on outcomes in these patients was assessed. A strong expression of Necl‐5 by cancer cells was observed in 43 of the 63 tumors. The overexpression of Necl‐5 by cancer cells was significantly associated with lymph node metastasis (P = 0.0398), TNM staging (P = 0.0367), and the bronchioloalveolar carcinoma ratio of tumors (P = 0.0423). Furthermore, the disease‐free survival rate in patients with positive Necl‐5 overexpression was significantly lower than that in patients with negative Necl‐5 overexpression (P = 0.0004). Multivariate survival analysis revealed Necl‐5 expression to be an independent risk factor for an unfavorable outcome (P = 0.0294). Additionally, an analysis including only the stage I cases revealed that the disease‐free survival rate of the Necl‐5‐positive group was significantly lower than that of the Necl‐5‐negative group (P = 0.0192). These results indicate that Necl‐5 plays a role in mediating tumor cell invasion and that the overexpression of Necl‐5 in cancer cells has clinical significance for prognostic evaluation of patients with primary pulmonary adenocarcinoma.(Cancer Sci 2010; 101: 1326–1330)