This study demonstrates that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox-LDL-positive macrophages. These observations suggest that increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions.

Background-Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes. Methods and Results-Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (nϭ45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (PϽ0.0001) in ruptured plaques than in eroded plaques.

Passive smoking substantially reduced CFVR in healthy nonsmokers. This finding provides direct evidence that passive smoking may cause endothelial dysfunction of the coronary circulation in nonsmokers.

Background-Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. Methods and Results-Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90°for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (PϽ0.0001). Moreover, the average number of calcium deposits within an arc of Ͻ90°per patient was significantly higher in AMI than in SAP (PϽ0.0005; meanϮSD, AMI 1.4Ϯ1.3, SAP 0.5Ϯ0.8). Conversely, calcium deposits were significantly longer in SAP patients (PϽ0.0001; meanϮSD, AMI 2.2Ϯ1.6, UAP 1.9Ϯ1.8, and SAP 4.3Ϯ3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. Conclusions-Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Objective: To investigate whether concentrations of plasma adiponectin constitute a significant coronary risk factor, with particular focus on the relation between plasma concentrations of adiponectin and the development of acute coronary syndrome (ACS). Subjects and methods: Plasma concentrations of adiponectin were measured in 123 patients with coronary artery disease (CAD) and in 17 control participants. Patients were divided into three groups according to condition type: acute myocardial infarction (AMI) group (n = 59), unstable angina pectoris (UAP) group (n = 28), and stable angina pectoris (SAP) group (n = 36). Results: Plasma concentrations of adiponectin correlated negatively with body mass index (r = 20.18, p , 0.05), serum triglyceride (r = 20.25, p , 0.01), and fasting glucose concentrations (r = 20.21, p , 0.05), but correlated positively with age (r = 0.26, p , 0.01), high density lipoprotein cholesterol concentrations (r = 0.35, p , 0.01), and low density lipoprotein particle size (r = 0.37, p , 0.01). Plasma concentrations of adiponectin in patients with ACS, in both the AMI and UAP groups, were significantly lower than those in patients with SAP and in the control group (ACS, 6.5 (3.0) mg/ml; SAP, 11.3 (5.9) mg/ml; control 12.8 (4.3) mg/ml; p , 0.01). Additionally, plasma concentrations of adiponectin in patients with CAD (7.9 (4.6) mg/ml, p , 0.01) were significantly lower than in the control group. There were, however, no significant differences between patients with SAP and the control group (p = 0.36). Multiple logistic regression analysis showed that smoking, fasting glucose concentration, and low log adiponectin concentration correlated independently with the development of an ACS. Conclusions: The findings suggest that measurement of plasma concentrations of adiponectin may be of use for assessing the risk of CAD and may be related to the development of ACS.

Objective-Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium. Methods and Results-The human VEGF 165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, ␣-smooth muscle actin-positive cells were most increased in the VEGF group. Key Words: angiogenesis Ⅲ gene therapy Ⅲ myocardial infarction Ⅲ stem cell Ⅲ transplantation C ell transplantation has become a promising novel therapy for ischemic heart disease and heart failure. Recent studies have revealed that various types of cells are effective in cell transplantation after myocardial infarction (MI), such as skeletal myoblasts, 1,2 smooth muscle cells, 3 and bone marrow mononuclear cells. 4 Bone marrow mononuclear cells are especially useful because they contain, among various lineage cells, hematopoietic cells and endothelial progenitor cells; therefore they have the ability to induce angiogenesis in ischemic tissue. A reported clinical trial of cell transplantation with skeletal myoblasts and mononuclear bone marrow cells showed that such therapies can have cardioprotective and angiogenic effects after MI. 5,6 However, selection of the most appropriate cell types for transplantation is controversial. Conclusions-ThisMesenchymal stem cells (MSCs) are isolated from bone marrow mononuclear cells and can be expanded ex vivo. Under appropriate culture conditions, MSCs have the potential to terminally differentiate into osteocytes, chondrocytes, adipocytes, tenocytes, myotubes, astrocytes, hematopoietic supporting stroma, and endothelial cells. 7 MSCs have also been used in a model of cell transplantation, 8,9 showing that these cells could differentiate into myogenic cells. Therefore, MSCs have many characteristics that make them useful for cellular therapy.Vascular endothelial growth factor (VEGF) is a strong therapeutic reagent for treating ischemia by inducing angiogenesis. 10 It has been reported that direct intramyocardial gene transfer results in localized enhancement of VEGF levels and successful angiogenesis in animal models of MI. 11 Furthermore, recent h...

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We previously identified testicular protein kinase 1 (TESK1), which phosphorylates cofilin and induces actin cytoskeletal reorganization. We now report identification and characterization of another member of a TESK family, testicular protein kinase 2 (TESK2), with 48% amino acid identity with TESK1. Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesions. Both TESK1 and TESK2 are highly expressed in the testis, but in contrast to TESK1, which is predominantly expressed in testicular germ cells, TESK2 is expressed predominantly in nongerminal Sertoli cells. Thus, TESK1 and TESK2 seem to play distinct roles in spermatogenesis. In HeLa cells, TESK1 was localized mainly in the cytoplasm, whereas TESK2 was localized mainly in the nucleus, which means that TESK1 and TESK2 likely have distinct cellular functions. Because the kinase-inactive mutant of TESK2 was localized in the cytoplasm, nuclear/cytoplasmic localization of TESK2 depends on its kinase activity. A TESK2 mutant lacking the C-terminal noncatalytic region had about a 10-fold higher kinase activity in vitro and, when expressed in HeLa cells, induced punctate actin aggregates in the cytoplasm and unusual condensation and fragmentation of nuclei, followed by apoptosis. Thus, we propose that the C-terminal region plays important roles in regulating the kinase activity and cellular functions of TESK2.The dynamics of polymerization/depolymerization of actin filaments and their remodeling are essential for cell movement, adhesion, and division (1). Cofilin and actin-depolymerizing factor (ADF) 1 play an essential role in the rapid turnover of actin filaments and actin-based cytoskeletal reorganization by stimulating depolymerization and severance of actin filaments (2-4). As the activity of cofilin/ADF is negatively regulated by phosphorylation at Ser-3 (5), enzymes phosphorylating cofilin/ ADF seem to play important roles in actin filament dynamics. We and other investigators provide evidence that LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) (6 -8) phosphorylate cofilin/ADF specifically at Ser-3 and induce actin cytoskeletal reorganization by phosphorylating and inactivating cofilin (9, 10). LIM kinases are activated in cultured cells by Rho family small GTPases Rac, Rho, and Cdc42 (9 -11), this activation mediated by downstream effectors p21-activated kinase (PAK) and Rho-associated kinase, by phosphorylation of Thr-508 of LIMK1 or Thr-505 of LIMK2 (12-16).Testicular protein kinase 1 (TESK1) is a serine/threonine kinase with a structure composed of an N-terminal protein kinase domain and a C-terminal proline-rich region (17). The kinase domain of TESK1 is closely related to those of LIM kinases (17). We recently obtained evidence that TESK1, like LIM kinases, has the potential to phosphorylate cofilin/ADF specifically at Ser-3 and induces the formation of actin stress fibers and focal adhesions by phosphorylating cofilin/ADF (18). In contrast to LIM kinases, the kinase activity of TESK1 is...