eleterious left ventricular (LV) remodeling after myocardial infarction (MI) is the major cause of heart failure. Although therapeutic strategies designed to limit ventricular remodeling after MI can decrease the incidence of congestive heart failure and improve survival, 1 mechanisms of remodeling process remain not fully elucidated. At the cellular level, reactive oxygen species (ROS) and oxidative stress play a key role in regulating myocardial remodeling. 2,3 In the stressed heart, there is an increase in the production of superoxide from multiple sources such as mitochondria, 4 NADPH oxidase, 5 xanthine oxidase, 6 and nitric oxide (NO) synthase. 7,8 NO is a diffusible highly reactive gas formed by 3 NO synthase (NOS) isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The eNOS-derived NO serves to promote vascular homeostasis and might affect cardiac myocyte function. 9 However, NOS itself can generate superoxide under certain pathological conditions. 10 We have reported that transgenic overexpression of eNOS in apolipoprotein E knockout mice paradoxically increased vascular superoxide production because of enzymatic uncoupling of eNOS. 11 These findings could be explained by relative deficiency of the reducing cofactor of eNOS, tetrahydrobiopterin (BH4). BH4 plays a crucial role in facilitating electron transfer from eNOS reductase domain, maintaining the heme prosthetic group in its redox active form, and promoting formation of active NOS homodimer. Therefore, a relative lack of BH4 results in increased superoxide production by promoting eNOS uncoupling. 12,13 NO from eNOS was shown to protect the heart from various stimuli. Previous studies have shown that cardiac remodeling after MI was attenuated in transgenic mice overexpressing eNOS, 14,15 but deteriorated in mice deficient of the eNOS gene (eNOS KO mice). 16 Similarly, pressure overload-induced LV remodeling was exacerbated in eNOS KO mice. 17,18 Takimoto et al investigated the role of eNOS in the LV remodeling induced by transverse aortic constric- Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and ResultsRats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the n...

Abstract-The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca 2ϩ -independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overloadinduced cardiac dysfunction. Key Words: nectin-2 Ⅲ cell adhesion molecule Ⅲ intercalated disc Ⅲ heart failure Ⅲ pressure overload I n the mature heart, the intercalated discs are located at the bipolar ends of the rod-shaped cardiac myocytes and mediate mechanical and electric coupling between adjacent cardiac myocytes. 1 The intercalated disc mainly consists of 3 junctional complexes: adherens junctions (AJs), desmosomes, and gap junctions. The role of AJs in the intercalated disc is to anchor myofibrils and to transmit the force developed by the contracting myofibril to neighboring cardiac myocytes. Desmosomes provide structural support by anchoring the intermediate filament system, and gap junctions provide intercellular communication via ions and small molecules. Changes in the intercalated disc architecture have been reported in mouse models for dilated cardiomyopathy (DCM), such as muscle LIM protein knockout (KO) mice and tropomodulin-overexpressing mice. 2,3 On the other hand, the targeted ablation of N-cadherin, which is predominantly localized at AJs in the intercalated disc, in the murine adult was shown to result in the disassembly of the intercalated disc structure and to exhibit a DCM-...

Circ J 2009; 73: 955 -962 ndothelial dysfunction (ED) plays a critical role in the initiation and progression of atherosclerosis 1,2 and is associated with risk factors for coronary artery diseases, including smoking, hypertension, hyperlipidemia, diabetes mellitus and obesity. [3][4][5][6][7] Furthermore, endothelial function was demonstrated to serve as a predictor of cardiovascular events. 8,9 Therefore, the evaluation of endothelial function is important to determine the therapeutic strategy for atherosclerotic diseases.Clinically, endothelial function has mostly been evaluated by the extent of endothelium-dependent relaxation (EDR), which is almost exclusively mediated by nitric oxide (NO). Particularly, flow-mediated vasodilatation (FMD) induced by reactive hyperemia following the release of a forearmoccluding cuff is an established method for assessing endothelial function. 10 By using this technique, the relationships between coronary risk factors and the ED have been assessed in many clinical studies, and the close linkage has been reported between endothelial function of the brachial artery and that of the coronary arteries. 11 Now it is well recognized that the extent of ED depends on the burden of coronary risk factors. 12 There have been, however, no reliable plasma markers found for ED in humans. When EDR is used as a standard representing endothelial function, only limited numbers of clinical studies have shown a correlation between a given plasma marker and EDR. 13,14 Oxidative stress has been shown as an important factor leading to ED. Oxidative stress oxidizes tetrahydrobiopterin (BH4), an essential cofactor for endothelial type NO synthase (eNOS), to its oxidative form 7, 8-dihydrobiopterin (BH2) in vascular tissue, particularly in the endothelium. 15,16 The resultant relative deficiency of BH4 causes the uncoupling of the L-arginine-NO pathway (uncoupling of eNOS), which is at least partly involved in the ED in various vascular disorders. 16,17 In certain pathological conditions such as renal failure, changes in plasma BH4 and BH2 have been reported. 18 As oxidative stress is the major factor damaging endothelial (Received September 8, 2008; revised manuscript received December 19, 2008; accepted December 25, 2008; released Background: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. Methods and Results:In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients wi...