No abstract

No abstract

A previous report showed that the consumption of glutathione through oxidative stress activates the glutathione synthetic pathway, which is accompanied by production of ophthalmic acid from 2-aminobutyric acid (2-AB). We conducted a comprehensive quantification of serum metabolites using gas chromatography-mass spectrometry in patients with atrial septal defect to find clues for understanding myocardial metabolic regulation, and demonstrated that circulating 2-AB levels reflect hemodynamic changes. However, the metabolism and pathophysiological role of 2-AB remains unclear. We revealed that 2-AB is generated by an amino group transfer reaction to 2-oxobutyric acid, a byproduct of cysteine biosynthesis from cystathionine. Because cysteine is a rate-limiting substrate for glutathione synthesis, we hypothesized that 2-AB reflects glutathione compensation against oxidative stress. A murine cardiomyopathy model induced by doxorubicin supported our hypothesis, i.e., increased reactive oxygen species are accompanied by 2-AB accumulation and compensatory maintenance of myocardial glutathione levels. Intriguingly, we also found that 2-AB increases intracellular glutathione levels by activating AMPK and exerts protective effects against oxidative stress. Finally, we demonstrated that oral administration of 2-AB efficiently raises both circulating and myocardial glutathione levels and protects against doxorubicin-induced cardiomyopathy in mice. This is the first study to demonstrate that 2-AB modulates glutathione homeostasis in the myocardium.

Rationale: Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin ␣ V ␤ 3 . However, how the interaction between VEGFR2 and integrin ␣ V ␤ 3 is regulated is not clear. Objective:To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin ␣ V ␤ 3 , regulates the interaction between VEGFR2 and integrin ␣ V ␤ 3 , and to clarify the role of Necl-5 in the VEGF-induced angiogenesis. Key Words: cell adhesion molecules Ⅲ angiogenesis Ⅲ peripheral vascular disease A ngiogenesis plays an important role in diverse developmental, physiological, and pathological processes. Angiogenesis is triggered by the interaction of proangiogenic growth factors and extracellular matrix with their receptors. Vascular endothelial growth factor (VEGF) is a major proangiogenic agent that regulates multiple key steps of angiogenesis. VEGF exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2). The activity of VEGFR2 is regulated by direct interactions with other cell surface proteins, such as coreceptor neuropilins 1 and adhesion molecules, including VE-cadherin 2 and integrins. 3 Integrins, including integrin ␣ V ␤ 3 , are critically involved in angiogenesis and initiate signals that control cell migration, proliferation, and survival. 4 Receptors such as VEGFR2 and plateletderived growth factor (PDGF) receptor (PDGFR) interact with integrins, and these interactions exhibit synergistic effects and cooperatively regulate diverse intracellular signals that control key cell functions. 3,5,6 However, how the interaction between VEGFR2 and integrin ␣ V ␤ 3 through their extracellular regions is regulated is not known. Methods and Results:Original received September 15, 2011; revision received January 12, 2012; accepted January 18, 2012. In December 2011 Nectins and nectin-like molecules (Necls) are immunoglobulinlike cell adhesion molecules that are essential for the formation of cell-cell adhesions, and these molecules regulate a variety of cellular functions, including cell polarization, differentiation, movement, proliferation, and survival. 7,8 Necls comprise a family with 5 members, Necl-1 to -5, and among these, Necl-5 exhibits distinctive expression profiles. Necl-5 was originally identified as human poliovirus receptor (PVR), also termed CD155, 9,10 and as rodent Tage4, which is overexpressed in rodent colon carcinoma. 11,12 Necl-5 is expressed ubiquitously, but its expression level is extremely low in most adult organs in rodents. 13,14 However, it becomes upregulated in the developing or regenerating liver 15,16 and transformed cells. 17,18 In NIH3T3 cells, Necl-5 forms a complex with integrin ␣ V ␤ 3 and PDGFR, and the formation of this complex enhances cell movement and proliferation. 19 However, the function of Necl-5 and its mode of action in vascular endothelial ...