Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells.

BACKGROUND: The regulatory molecule for cell life span, telomerase, was modified by human telomerase reverse transcriptase (hTERT) gene transfer to investigate its effect on regenerative properties of endothelial progenitor cells (EPCs) in neovascularization. METHODS AND RESULTS: Telomerase activity was enhanced in hTERT-transduced EPCs (Td-TERTs) (1.2-fold versus no transduced EPCs [no-Td] and 1.2-fold versus GFP-transduced EPCs [Td/GFPs] at day 8; 5.2-fold versus no-Td and 4.8-fold versus Td/GFP at day 21, respectively) Mitogenic capacity in Td/TERTs exceeded that in Td/GFPs at day 8 (0.62+/-0.02 versus 0.53+/-0.01, respectively; P<0.01). Vascular endothelial growth factor-induced cell migration in EPCs was markedly enhanced by hTERT overexpression (Td/TERTs versus Td/GFPs, 292+/-12 versus 174+/-6 cells, respectively; P<0.01). hTERT overexpression has rescued EPCs from starvation-induced cell apoptosis, an outcome that was further enhanced in response to vascular endothelial growth factor. The colony appearance of totally differentiated endothelial cells (tdECs) was detected before day 30 only in Td/TERT, whereas no tdEC colonies could be detected in both Td/GFPs and no-Tds. Finally, we investigated in vivo transplantation of heterologous EPCs. Td/TERTs dramatically improved postnatal neovascularization in terms of limb salvage by 4-fold in comparison with that of Td/GFPs; limb perfusion was measured by laser Doppler (0.77+/-0.10 versus 0.47+/-0.06; P=0.02), and capillary density (224+/-78 versus 90+/-40 capillaries/mm2; P<0.01). CONCLUSIONS: These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.

[Determination and utilisation of the plasmatic concentration of homocysteine in clinical practice]. / Determinación y utilización de la concentración plasmática de homocisteína en la práctica clínica.

Homocysteine is a methionine-derived amino acid and its metabolism depends on B12, B6 and B2 vitamins and folic acid. The total homocysteine plasmatic concentration can be measured in most laboratories by means of enzymeimmunoassays. Hyperhomocysteinemia may be caused by genetic defects of the enzymes involved in its metabolism, nutritional deficiencies or absorption deficiencies of the vitamin cofactors of these enzymes, chronic diseases or administration of some drugs. An increase in the total plasmatic concentration of homocysteine represents a sensitive marker of folate and cobalamin deficiencies as well as an independent risk factor of cardiovascular disease. Furthermore, total plasmatic concentrations of homocysteine are related to the development of congenital malformations, pregnancy complications, psychiatric diseases and to cognitive impairment in the elderly. Therefore, the measurement of the concentration of homocysteine has a notable clinical interest, which may increase in future if it is confirmed that the association with these disorders is causal and that they can be prevented by treating hyperhomocysteinemia.

[Effects of statins on angiogenesis and vasculogenesis]. / Efecto de las estatinas en la inducción de angiogénesis y vasculogénesis.

Statins promote the proliferation, migration, and survival of endothelial cells and bone marrow-derived endothelial progenitor cells (angioblasts) by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) pathway. Like vascular endothelial growth factor (VEGF), the statins promote angiogenesis and vasculogenesis. Therefore, Akt activation may explain some of the beneficial effects of the statins, including postnatal neovascularization.

[Evolution of systolic function and myocardial perfusion, evaluated by gated-SPECT, in the first year after acute myocardial infarction]. / Evolución de la función sistólica y de la perfusión micárdica valorada mediante gated-SPECT durante el primer año despuésde un infarto agudo de miocardio.

INTRODUCTION AND OBJECTIVES: Systolic function and myocardial perfusion are evaluated before hospital discharge and can change during follow-up. The purpose of this study was to evaluate these parameters by gated-SPECT in the first year after acute myocardial infarction. PATIENTS AND METHOD: We studied 74 consecutive patients with a first uncomplicated acute myocardial infarction (49 infero-lateral and 25 anterior) by stress-rest 99mTc-tetrofosmin and rest-gated-SPECT before hospital discharge (6-8 days after admission) and one year after myocardial infarction. RESULTS: The ejection fraction (EF) increased > 5% in 51% of infero-lateral infarcts and 28% of non-revascularized anterior infarcts. EF increased significantly (48.4 8% to 54.6 8.7%; p < 0.0001, mean difference: 6.2; 95% IC, 2.8-9.5) and systolic volume decreased (51.3 19.2 ml to 44.3 19.4 ml; p = 0.001; mean diff.: 7.67; 95% IC, 1.5-13.8) in infero-lateral infarctions. The rest perfusion index in the necrotic region improved (2.3 0.57 to 2.17 0.58; p = 0.004; mean diff.: 0.18; 95% IC, 0.003-0.36) in infero-lateral infarcts and the ischemia index remained unchanged between the first and second studies. CONCLUSIONS: Left ventricular systolic function can change during the first year of evolution, a significant improvement being seen in infero-lateral infarctions. The ejection fraction increased > 5% in half of these patients, as opposed to only a quarter of anterior infarctions. This improvement was associated to increased myocardial perfusion at rest.