Da Disfunção Endotelial à Oclusão Vascular Papel do Sistema Renina - Angiotensina

There is a body of evidence that supports the important role of the renin-angiotensin system (RAS) in atherosclerotic disease and in the cardiovascular disease continuum: from endothelial dysfunction to vascular occlusion. In the earlier stages of vascular disease, the RAS promotes functional changes, of which endothelial dysfunction is the best example. The deposition of atherogenic lipoproteins in the intima, their oxidative modification and the onset and amplification of the inflammatory response strengthens the atherogenic role of the RAS. Inflammatory cells are one of the main sources of angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) in the vascular wall, in a process that leads to structural changes in the artery and progression of atherosclerotic disease. Ang II promotes the migration of vascular smooth muscle cells and their phenotypic differentiation in synthesis that accelerates vascular disease. By modulating the inflammatory response and, in general, all the elements of the plaque, Ang II plays a part in its instability, in the onset of acute events and in the promotion of the local prothrombotic state that leads to infarction.

Impacto da Combinação de Terapêutica Farmacológica na Mortalidade em Doentes com Síndrome Coronária Aguda

INTRODUCTION: Conventional risk stratification after acute myocardial infarction is usually based on the extent of myocardial damage and its clinical consequences. However, nowadays, more aggressive therapeutic strategies are used, both pharmacological and invasive, with the aim of changing the course of the disease. OBJECTIVES: To evaluate whether the number of drugs administered can influence survival of these patients, based on recent clinical trials that demonstrated the benefit of each drug for survival after acute coronary events. METHODS: This was a retrospective analysis of 368 consecutive patients admitted to our ICU during 2002 for acute coronary syndrome. A score from 1 to 4 was attributed to each patient according to the number of secondary prevention drugs administered--antiplatelets, beta blockers, angiotensin-converting enzyme inhibitors and statins--independently of the type of association. We evaluated mortality at 30-day follow-up. RESULTS: Mean age was 65 +/- 13 years, 68% were male, and 43% had ST-segment elevation acute myocardial infarction. Thirty-day mortality for score 1 to 4 was 36.8%, 15.6%, 7.8% and 2.5% respectively (p < 0.001). The use of only one or two drugs resulted in a significant increase in the risk of death at 30 days (OR 4.10, 95% CI 1.69-9.93, p = 0.002), when corrected for other variables. There was a 77% risk reduction associated with the use of three or four vs. one or two drugs. The other independent predictors of death were diabetes, Killip class on admission and renal insufficiency. CONCLUSIONS: The use of a greater number of secondary prevention drugs in patients with acute coronary syndromes was associated with improved survival. A score of 4 was a powerful predictor of mortality at 30-day follow-up

Effect of Efavirenz on High-Density Lipoprotein Antioxidant Properties in HIV-Infected Patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In previous work, we showed a long-term and concentration-dependent beneficial effect of the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) on high-density lipoproteins (HDL) in human immunodeficiency virus (HIV)-infected patients. * Furthermore, it has been suggested that instead of the current practice of only measuring HDL-chelesterol values, the evaluation of HDL function, namely its antioxidant properties, might be an improved tool for identifying subjects at increased risk for cardiovascular events. * Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is responsible for HDL antioxidant function. WHAT THIS STUDY ADDS: * In the present work, we studied the effect of EFV on the activity of PON-1 and showed, for the first time, that EFV-based antiretroviral therapy is associated with a better antioxidant function, i.e. with a higher PON-1 activity. AIMS: A long-term and concentration-dependent beneficial effect of efavirenz (EFV) on cholesterol associated with high-density lipoprotein (HDL-c) in human immunodeficiency virus (HIV)-infected patients has been documented. Furthermore, it has been suggested that, instead of the current practice of only measuring HDL-c values, the evaluation of HDL quality might be an improved tool for identifying subjects at increased risk of cardiovascular events. Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is involved in the onset of cardiovascular disease and responsible for HDL antioxidant function. The aim of the present study was to investigate the effect of EFV on the circulating activity of PON-1 in HIV-infected patients. METHODS: The patients included were adults with a documented HIV-1 infection, nontreated or treated with antiretroviral regimens including EFV 600 mg once daily as first therapeutic regimen for at least 3 months. The influence of treatment with EFV, HDL-c and CD4 cell count on PON-1 activity was analysed. RESULTS: HIV-infected White patients treated with EFV had higher PON-1 activity [77.35 U l(-1) (65.66, 89.04)] (P < 0.05) and higher PON-1 activity : HDL-c ratio [1.88 (1.49, 2.28)] (P < 0.01) than untreated patients. PON-1 activity was higher in Black patients (P < 0.001) and in patients with a CD4 cell count >500 cells ml(-1) (P= 0.0120). CONCLUSIONS: EFV-based antiretroviral regimens are associated with HDL particles with a better antioxidant function, i.e. with a higher PON-1 activity. The PON-1 activity of Black patients is higher than that found in Whites regardless of treatment. Ethnicity should be taken into consideration when studying drug effects on PON-1 activity.

Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.