Tomoya Kitamura

Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin.

The serine/threonine protein kinase Akt is involved in a variety of cellular processes including cell proliferation, survival, metabolism and gene expression. It is essential in vascular endothelial growth factor (VEGF)-mediated angiogenesis; however, it is not known how Akt regulates the migration of endothelial cells, a crucial process for vessel sprouting, branching and the formation of networks during angiogenesis. Here we report that Akt-mediated phosphorylation of Girdin, an actin-binding protein, promotes VEGF-dependent migration of endothelial cells and tube formation by these cells. We found that exogenously delivered adenovirus harbouring Girdin short interfering RNA in Matrigel embedded in mice, markedly inhibited VEGF-mediated angiogenesis. Targeted disruption of the Girdin gene in mice impaired vessel remodelling in the retina and angiogenesis from aortic rings, whereas Girdin was dispensable for embryonic vasculogenesis. These findings demonstrate that the Akt/Girdin signalling pathway is essential in VEGF-mediated postneonatal angiogenesis.

Combined assessment of left ventricular dyssynchrony and contractility by speckled tracking strain imaging: A novel index for predicting responders to cardiac resynchronization therapy

BACKGROUND Mechanical dyssynchrony is an important factor in the response to cardiac resynchronization therapy (CRT). However, no echocardiographic measure can improve prediction of case selection for CRT. OBJECTIVE The purpose of this study was to assess the efficacy of a newly combined echocardiographic index for ventricular dyssynchrony and contractility using speckled tracking strain analysis to predict responders to CRT. METHODS Forty-seven patients with severe heart failure in New York Heart Association functional class III/IV, left ventricular ejection fraction </=35%, and QRS duration >/=130 ms were included in the study. Echocardiography was performed, and a novel index (i-Index), the product of radial dyssynchrony and radial strain, was calculated. Responder to CRT was defined as a patient with a >/=15% decrease in left ventricular end-systolic volume at 6-month follow-up. RESULTS Thirty-two patients (68%) were classified as responders. The i-Index was significantly higher in responders than in nonresponders (3,450 +/- 1180 vs 1,481 +/- 841, P <.001). The area under receiver operator characteristic curve was 0.92 for the i-Index, which was better than the index of radial dyssynchrony only (0.74). A cutoff value of i-Index >2,000 predicted responders with 94% sensitivity and 80% specificity. The index using only radial dyssynchrony had 81% sensitivity and 53% specificity. Furthermore, i-Index decreased in responders (1,985 +/- 1261, P <.001) but not in nonresponders (1,684 +/- 866, P = .48). CONCLUSION Our findings suggest that a novel combined index by radial strain echocardiography might be a predictor of response to CRT. The value of this novel echocardiographic index requires further assessment in larger studies.

The number and function of circulating CD34+CD133+ progenitor cells decreased in stable coronary artery disease but not in acute myocardial infarction

Objective Circulating CD34+CD133+ cells are one of the main sources of circulating endothelial progenitor cells (EPCs). Age is inversely related to the number and function of CD34+CD133+ progenitor cells in stable coronary artery disease (CAD), but the relationship remains unclear in acute myocardial infarction (AMI). The authors aimed to clarify how ageing affects the number and function of mobilised CD34+CD133+ progenitor cells in AMI. Design and results Circulating CD34+CD133+ progenitor cells were measured by flow cytometry. Measurements were made at admission for CAD, or on day 7 after the onset of AMI. In stable CAD (n=131), circulating CD34+CD133+ cells decreased with age (r=−0.344, p<0.0001). In AMI, circulating CD34+CD133+ cells did not correlate with age (n=50), and multivariate analysis revealed that the decreased number of circulating CD34+CD133+ cells was associated with male sex and higher peak creatinine kinase. The ability to give rise to functional EPCs, which show good migratory and tube-forming capabilities, deteriorated among stable CAD subjects (n=10) compared with AMI subjects (N=6). Conclusions In stable CAD, the number and function of circulating CD34+CD133+ progenitor cells decreased with age, whereas those mobilised and circulating in AMI did not.