Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / "May 2000." Typescript. Vita. Includes bibliographical references (leaves 152-178). Also available on the Internet.

Σκοπός της συγκεκριμένης ερευνητικής εργασίας ήταν η αποσαφήνιση του ρόλου της αλβουμίνης στην πρόκληση νεφρικής ίνωσης, διαμέσου του συστήματος ΕΤ-1/ΝΟ. Για το λόγο αυτό πραγματοποιήθηκαν in vitro πειράματα, στα οποία χρησιμοποιήθηκαν ΗΚ-2 κύτταρα και διερευνήθηκε η επίδραση της αλβουμίνης στην αλλαγή της μορφολογίας, στην προσκόλληση, στη μετανάστευση, στην παραγωγή ΝΟ και cGMP, στην έκφραση των et-1, etr-a, etr-b, enos και inos και τη συσσώρευση των αντίστοιχων πρωτεϊνών, καθώς επίσης και των πρωτεϊνών τουμπουλίνης και ακτίνης και τέλος στην ενζυμική δραστικότητα της μεταλλοπρωτεϊνάσης MMP-2. Προέκυψε ότι η αλβουμίνη τροποποιεί την έκφραση των γονιδίων et-1 και των υποδοχέων της etr-a και etr-b, των συνθετασών του ΝΟ, enos και inos, τη συσσώρευση των αντίστοιχων πρωτεϊνών, του cGMP, καθώς και του παραγόμενου NO. Επίσης, η αλβουμίνη δεν επηρεάζει τη συσσώρευση της ακτίνης, ενώ προκαλεί ελάττωση της συσσώρευσης της τουμπουλίνης και αναδιοργάνωση του κυτταροσκελετού. Τέλος, επάγει την ενζυμική δραστικότητα της MMP-2 και τον πολλαπλασιασμό, ενώ εμποδίζει τη μετανάστευση και την προσκόλληση των HK-2. / The aim of this research was the elucidation of the role of albumin in the induction of renal fibrosis, through the activation of the ET-1/NO system. We performed in vitro experiments using HK-2 cells (human proximal tubular epithelial cells) and we studied the morphological alterations, cell adhesion, migration, production of NO and cGMP, expression of et-1, etr-a, etr-b, enos and inos and the accumulation of the subsequent proteins, as well as tubulin and actin. Finally we studied the enzymic activity of metalloproteinase MMP-2. Albumin was found to alter the expression of et-1, etr-a, etr-b and enos and the accumulation of the subsequent proteins. Moreover, it affects the amount of the synthesized and secreted cGMP and NO, reduces the accumulation of tubulin, while having no effect on the accumulation of actin and participates in the reorganization of the cytoskeleton. Furthermore, albumin alters the enzymic activity of MMP-2, induces cell proliferation and inhibits the adhesion and migration of the HK-2 cells.

Η ενδοθηλίνη-1 (ΕΤ-1) εμπλέκεται στην παθογένεση του βρογχικού άσθματος και της χρόνιας αποφρακτικής πνευμονοπάθειας (ΧΑΠ). Η ΕΤ-1 είναι μέλος μίας οικογενείας πεπτιδίων 21 αμινοξέων. Αρχικά σχηματίζεται ένα πεπτίδιο 208 αμινοξέων, η προ-προενδοθηλίνη. Στη συνέχεια, με τη δράση της μετατρεπτάσης της φουρίνης, σχηματίζεται ένα πεπτίδιο 38 αμινοξέων η big-ενδοθηλίνη και στη συνέχεια με τη δράση του μετατρεπτικού ενζύμου ενδοθηλίνης μετατρέπεται σε πεπτίδιο 21 αμινοξέων την ενδοθηλίνη η οποία κυκλοφορεί στο πλάσμα. Η ΕΤ-1 συνδέεται σε δύο τύπους υποδοχέων Α και Β. Οι υποδοχείς τύπου Α επικρατούν στα λεία μυϊκά κύτταρα των αγγείων και των βρόγχων. Οι υποδοχείς τύπου Β επικρατούν κυρίως στα ενδοθηλιακά κύτταρα και στα λεία μυϊκά κύτταρα των αεραγωγών. Κύριες θέσεις παραγωγής της ΕΤ-1 είναι το βρογχικό επιθήλιο, το ενδοθήλιο των πνευμονικών αρτηριών, τα ενδοθηλιακά και τα λεία μυϊκά κύτταρα των αγγείων. Οι δράσεις της ΕΤ-1 στους βρόγχους αφορούν στη συστολή των λείων μυϊκών ινών των αεραγωγών, στην αναδιαμόρφωση του τοιχώματος των βρόγχων, στην έκκριση βλέννης, στη διέγερση-απελευθέρωση άλλων μεσολαβητών φλεγμονής, σε μεταβολές στην διαπερατότητα των μικροαγγείων των αεραγωγών, στην νευρορρύθμιση και τέλος στην υπεραντιδραστικότητα των αεραγωγών. Στην παρούσα μελέτη εξετάστηκαν τα επίπεδα ΕΤ-1 ορού αρτηριακού αίματος 40 ασθματικών ασθενών στην έξαρση και στην ύφεση της νόσου. Σύμφωνα με τα αποτελέσματα της μελέτης μας, τα επίπεδα της ΕΤ-1 στην έξαρση της νόσου ήταν αυξημένα σε σχέση με αυτά στην ύφεση. Υπάρχει θετική συσχέτιση ανάμεσα στην ΕΤ-1 έξαρσης και ύφεσης ανά ασθενή. Αποδείχθηκε αρνητική συσχέτιση ανάμεσα στην ΕΤ-1 έξαρσης και SatO2 έξαρσης καθώς και στην ΕΤ-1 ύφεσης και SatO2 ύφεσης, καθώς και μεταξύ ΕΤ-1 έξαρσης, FEV1 και FVC. Δεν βρέθηκε στατιστικά σημαντική συσχέτιση μεταξύ ΕΤ-1 και καπνίσματος. Οι άντρες είχαν υψηλότερα επίπεδα ΕΤ-1 κατά την έξαρση της νόσου και κατά την ύφεση από ό,τι οι γυναίκες. Δεν υπάρχει στατιστικά σημαντική συσχέτιση ανάμεσα στην χρόνια θεραπεία με κορτικοστεροειδή και στα επίπεδα ΕΤ-1 έξαρσης. Τέλος τα επίπεδα της ΕΤ-1 ύφεσης δεν συσχετίστηκαν με την διάρκεια ούτε τη δοσολογία της θεραπείας έξαρσης με κορτικοστεροειδή. Πιθανώς, η επινόηση ανταγωνιστών υποδοχέων ΕΤ-1, εκλεκτικών ή μη, να έχει ιδιαίτερη σημασία στην θεραπεία του βρογχικού άσθματος υπό την έννοια της πρόληψης πνευμονικής υπερτάσεως σε ασθενείς με βαρύ άσθμα. / Endothelin-1 (ET-1) has been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). ET-1 is a member of a family of peptides of 21 amino-acids. The initial stage in the synthesis of ET-1 involves the formation of a 208-amino acid peptide, named pre-proendothelin, which is processed, via the activity of furin, to the 38-amino acid prohornon, big-endothelin-1, which is secreted and circulates in plasma. Big-ET-1 is then cleaved between Trp and Val to form ET-1 via an endopeptidase called “ET converting enzyme”. ET-1 binds to two types of receptors A and B. Receptors type A are expressed on vascular smooth muscle cells of vessels and bronchuses. Receptors type B are expressed predominantly on endothelial cells and to a much lesser extend on vascular smooth muscle cells. Main places of ET- 1 production are the bronchial epithelium, the epithelium of pulmonary arteries, the vascular endothelial and smooth muscle cells. ET-1 induces airway smooth muscle cell contraction, airway wall remodeling, mucus secretion, stimulation of the release of other mediators, changes in airway microvascular permeability neuromodulation and finally airway hyperresponsiveness. In the present study, we examined ET-1 arterial blood levels of 40 asthmatic patients during the exacerbation and the remission of the disease. According to the results of our study, the ET-1 levels during the exacerbation of the disease were increased concerning them, during the remission. ET-1 levels were negatively statistically significantly correlated with SatO2 during the exacerbation and the remission of the disease as well as between ET-1 levels, FEV1 and FVC during the exacerbation of the disease. There were not found statistically significant correlation between ET-1 and smoking. Men had higher ET-1 levels during the exacerbation and the remission of the disease, than women. There were not statistically significant correlation between chronic treatment with corticosteroides and the ET-1 exacerbation levels, as well as between treatment with corticosteroides during the exacerbation and the ET-1 remission levels. Probably, the invention of ET-1 receptor inhibitors (selected or not) has a particularly important meaning concerning treatment of bronchial asthma under the meaning of prevention of pulmonary hypertension in patients with heavy asthma.

Εισαγωγή: Τα επίπεδα της ενδοθηλίνης-1 (ΕΤ-1) στο περιφερικό πλάσμα αυξάνονται μετά από αγγειοπλαστική των στεφανιαίων αρτηριών με μπαλόνι (PTCA) λόγω μηχανικής βλάβης του ενδοθηλίου των στεφανιαίων αρτηριών κατά την επέμβαση. Η ΕΤ-1 έχει ανεβρεθεί σε ανθρώπινα ενδοκαρδιακά και μυοκαρδιακά κύτταρα. Δεν είναι γνωστό αν η ΕΤ-1 αυξάνεται μετά από θερμική βλάβη του μυοκαρδίου κατά τη διενέργεια κατάλυσης αρρυθμιών με ρεύμα ραδιοσυχνότητας. Μέθοδοι: Προσδιορίσαμε τα επίπεδα ΕΤ-1 στο περιφερικό πλάσμα πριν την εκτέλεση, αμέσως μετά και στις 2 και 6 ώρες μετά από PTCA (31 ασθενείς), και κατάλυση με ρεύμα ραδιοσυχνότητας (16 ασθενείς). Δεκαπέντε ασθενείς που υποβλήθηκαν σε διαγνωστικό καθετηριασμό και 13 ασθενείς που υποβλήθηκαν σε διαγνωστική ηλεκτροφυσιολογική μελέτη χρησιμοποιήθηκαν ως μάρτυρες. Αποτελέσματα: Τα επίπεδα ΕΤ-1 στο περιφερικό πλάσμα αυξήθηκαν σημαντικά αμέσως μετά την PTCA σε σχέση με τα επίπεδα πριν την επέμβαση (55.1±20.1 vs. 42.7±14.9 pg/ml, p<0.01) και στις 2 ώρες μετά την κατάλυση με ρεύμα ραδιοσυχνότητας σε σχέση με εκείνα πριν την επέμβαση (98.0±11.7 vs. 53.0±17.4 pg/ml, p<0.01). Στις 2 ώρες μετά την PTCA και στις 6 ώρες μετά την κατάλυση με ρεύμα ραδιοσυχνότητας τα επίπεδα ΕΤ-1 πλάσματος δεν διέφεραν στατιστικά από τα επίπεδα πριν την επέμβαση. Στις ομάδες ελέγχου (στεφανιογραφία και ηλεκτροφυσιολογική μελέτη) δεν παρατηρήθηκε αύξηση της ΕΤ-1. Η καμπύλη κινητικής της ΕΤ-1 κατέδειξε πολύ υψηλότερες τιμές ΕΤ-1 στους ασθενείς που υποβλήθηκαν σε κατάλυση με ρεύμα ραδιοσυχνότητας σε σχέση με αυτούς που υποβλήθηκαν σε PTCA (p<0.001). Τα επίπεδα ΕΤ-1 αμέσως μετά την PTCA συσχετίζονταν με το ολικό γινόμενο πίεσης-χρόνου διαστολής του μπαλονιού κατά την αγγειοπλαστική (r=0.56, p<0.01). Δεν υπήρχε συσχέτιση των επιπέδων ΕΤ-1 και του αριθμού των βλαβών που προκλήθηκαν κατά τη διενέργεια κατάλυσης με ρεύμα ραδιοσυχνότητας. Κανένας ασθενής στην ομάδα της PTCA δεν εμφάνισε οξεία ισχαιμία ή άλλη σοβαρή επιπλοκή μετά την επέμβαση. Κανένας ασθενής στην ομάδα της κατάλυσης με ρεύμα ραδιοσυχνότητας δεν εμφάνισε αρρυθμία ή άλλες ανεπιθύμητες επιπλοκές μετά την επέμβαση. Συμπεράσματα: Εκτός από τη μηχανική πίεση του ενδοθηλίου κατά τη διενέργεια PTCA, η βλάβη του ενδομυοκαρδίου από τη θερμική ενέργεια που χρησιμοποιείται κατά την κατάλυση με ρεύμα ραδιοσυχνότητας αντιπροσωπεύει άλλον έναν μηχανισμό αύξησης της ενδογενούς παραγωγής ενδοθηλίνης. Η πιθανή προέλευση αυτής της ΕΤ-1 είναι τα κύτταρα του ενδοκαρδίου ή/και μυοκαρδίου. Η αύξηση της ΕΤ-1 μετά την κατάλυση με ρεύμα ραδιοσυχνότητας είναι μεγαλύτερη και πιο καθυστερημένη σε σχέση με την αύξηση της ΕΤ-1 που παρατηρείται μετά PTCA. Παρόλαυτά δεν συνοδεύεται από ανεπιθύμητες κλινικές δράσεις στην άμεση περίοδο μετά την επέμβαση. / Background: Plasma levels of Endothelin-1 (ET-1) increase after coronary angioplasty (PTCA) due to endothelial injury during the procedure. ET-1 has been found in human endocardial and myocardial cells. It is not known whether ET-1 increases after thermal injury induced by radiofrequency ablation (RFA) lesions. Methods: We determined peripheral vein plasma ET-1 levels at baseline, immediately after, and at 2 and 6 hours post-procedure in 31 patients undergoing PTCA and 16 patients undergoing RFA. Patients subjected to diagnostic coronary angiography (n=15) and electrophysiologic study (n=13) served as controls. Results: ET-1 levels increased significantly from baseline immediately post-PTCA (55.1±20.1 vs. 42.7±14.9 pg/ml, p<0.01) and at 2 hours post-RFA (98.0±11.7 vs. 53.0±17.4 pg/ml, p<0.01) and returned to baseline at 2 hours post-PTCA and 6 hours post-RFA. There was no change in the control groups. ET-1 kinetics curve was significantly higher post-RFA compared to post-PTCA (p<0.001). ET-1 immediately post-PTCA correlated with total pressure-time product applied during the procedure (r=0.56, p<0.01). There was no correlation of ET-1 levels and the number of RFA applications. No patient developed ischemia post-PTCA. There were no complications or arrhythmia recurrence post-RFA. Conclusions: Endocardial thermal injury during RFA is another mechanism of endothelin increase apart from mechanical injury of the coronary endothelium during PTCA and represents further evidence for the existence of the peptide in the human endomyocardial cells. ET-1 increase is delayed and more pronounced post-RFA compared to post-PTCA. Despite that, it does not seem to have any clinical impact in the immediate post-RFA period.

Since its discovery in 1988 the powerful vasoconstrictor endothelin-1 (ET-1) has been widely implicated in the pathophysiology of chronic kidney disease (CKD) as well as the cardiovascular disease with which it is associated. ET receptor antagonists have favourable effects in experimental models of these conditions and orally acting antagonists are now licensed for the treatment of pulmonary arterial hypertension. However, there is a paucity of human data regarding the role of ET-1 in CKD. In this thesis, I have therefore explored the utility of ET-1 as a biomarker in CKD, and, using selective ET receptor antagonists, the beneficial renal and cardiovascular effects of ET receptor antagonism in CKD. I have shown that as glomerular filtration rate (GFR) declines plasma ET-1 increases linearly whereas urinary ET-1 shows an exponential increase. Furthermore, urinary ET-1 may be a useful marker of disease activity in patients with lupus nephritis. Its levels are high in those with biopsy-proven active renal inflammation and these fall with treatment. I have shown that in subjects with stable non-diabetic proteinuric CKD, acute selective ETA receptor antagonism reduces blood pressure and arterial stiffness and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. Importantly, these effects are seen on top of those achieved with maximal therapy with angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers. Following a study confirming unchanged pharmacokinetics in CKD, I have used an oral selective ETA receptor antagonist to show that the reductions in BP, arterial stiffness and proteinuria seen in my acute studies are maintained longer term. This results of this study also suggest that the mechanism for the reduction in proteinuria is haemodynamic and relates to a reduction in GFR and filtration fraction. In summary, these studies suggest that ET-1 may act as a potential biomarker of renal inflammation, and confirm its role in the pathophysiology of the systemic and renal vasoconstriction seen in CKD. They also suggest that selective ETA receptor antagonism may provide a novel therapeutic approach in proteinuric CKD on top of standard therapies. Larger and longer term studies are now warranted to confirm this potential.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Introdução. A prática regular do exercício de força (EF) está associada a adaptações metabólicas, neuromusculares e cardiovasculares que repercutem de maneira positiva sobre a saúde e qualidade de vida de seus praticantes. No entanto, Indivíduos sedentários apresentam comprometimentos agudos na função endotelial após EF de alta intensidade. Objetivo. Avaliar a função endotelial de indivíduos sedentários de meia idade em resposta a diferentes intensidades do EF. Métodos. 11 indivíduos sedentários (40,1±3,9 anos; 27,3±1,4 kg/m2) realizaram EF em três condições experimentais: extensão de joelhos a 50% de 1RM (MI), 80% de 1RM (AI) e repouso na condição controle (CON). Foi realizada avaliação da vasodilatação mediada pelo fluxo (FMD) antes, 30 minutos após e 60 minutos após os protocolos. A quantificação das concentrações de NO2 e NO3 (NOx), endotelina-1 (ET-1) e TBARS foram realizadas antes, imediatamente após e 60 minutos após os protocolos. A pressão arterial foi mensurada antes e após os protocolos Resultados. A FMD aumentou significativamente 30 minutos após o exercício na condição MI (12,5± 4,10 para 17,2±3,9 %; p=0,01) bem como os níveis de NOx (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). A concentração de ET-1 aumentou imediatamente após na condição AI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). A elevação da pressão arterial não diferiu entre as condições MI e AI. As concentrações de TBARS não se alteraram ao longo dos protocolos. Conclusão. O EF de moderada intensidade aumenta a FMD e os níveis NOx após uma sessão aguda de exercício em indivíduos sedentários de meia idade, estes resultados sugerem que menores intensidades do EF são mais seguras ao iniciar um programa de exercícios. / Regular resistance exercise (RE) is associated with metabolic, neuromuscular and cardiovascular adaptation that results in improvement of quality of life and health. However, sedentary subjects have been showing an acute impairment on endothelial function after high intensity resistance exercise. The aim of this study was to evaluate the endothelial function in sedentary middle age men after RE in different intensities. Methods. Eleven middle age sedentary men (40,1±3,9 years; 27,3±1,4 kg/m2) performed RE in three different conditions: knee extension at 50% of one 1RM (MI), at 80% of 1RM (HI) and rest in the control group (CON). Flow mediated dilation (FMD) was assessed before, 30 and 60 minutes of exercise. Venus plasma concentration of ET-1 NOx and TBARS were measured before, immediately after and 60 minutes after exercise. Blood pressure was evaluated before and after exercise. Results. There was a significant improvement in FMD 30 minutes after exercise in the MI condition (12,5± 4,10 vs 17,2±3,9%; p= 0,016; p=0,01). The plasma NOx concentration was significant higher immediately after MI (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). There was a significant improvement in the plasma ET-1 concentration immediately after HI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). There was no significant difference in the BP between the experimental conditions (MI vs HI) and TBARS throughout the experimental conditions. Conclusions. Resistance exercise performed in moderate intensity improve endothelial function in sedentary middle aged men, there results suggest that lower intensities of RE could be safe for this population in the beginning of the exercise programs.

Introdução. A prática regular do exercício de força (EF) está associada a adaptações metabólicas, neuromusculares e cardiovasculares que repercutem de maneira positiva sobre a saúde e qualidade de vida de seus praticantes. No entanto, Indivíduos sedentários apresentam comprometimentos agudos na função endotelial após EF de alta intensidade. Objetivo. Avaliar a função endotelial de indivíduos sedentários de meia idade em resposta a diferentes intensidades do EF. Métodos. 11 indivíduos sedentários (40,1±3,9 anos; 27,3±1,4 kg/m2) realizaram EF em três condições experimentais: extensão de joelhos a 50% de 1RM (MI), 80% de 1RM (AI) e repouso na condição controle (CON). Foi realizada avaliação da vasodilatação mediada pelo fluxo (FMD) antes, 30 minutos após e 60 minutos após os protocolos. A quantificação das concentrações de NO2 e NO3 (NOx), endotelina-1 (ET-1) e TBARS foram realizadas antes, imediatamente após e 60 minutos após os protocolos. A pressão arterial foi mensurada antes e após os protocolos Resultados. A FMD aumentou significativamente 30 minutos após o exercício na condição MI (12,5± 4,10 para 17,2±3,9 %; p=0,01) bem como os níveis de NOx (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). A concentração de ET-1 aumentou imediatamente após na condição AI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). A elevação da pressão arterial não diferiu entre as condições MI e AI. As concentrações de TBARS não se alteraram ao longo dos protocolos. Conclusão. O EF de moderada intensidade aumenta a FMD e os níveis NOx após uma sessão aguda de exercício em indivíduos sedentários de meia idade, estes resultados sugerem que menores intensidades do EF são mais seguras ao iniciar um programa de exercícios. / Regular resistance exercise (RE) is associated with metabolic, neuromuscular and cardiovascular adaptation that results in improvement of quality of life and health. However, sedentary subjects have been showing an acute impairment on endothelial function after high intensity resistance exercise. The aim of this study was to evaluate the endothelial function in sedentary middle age men after RE in different intensities. Methods. Eleven middle age sedentary men (40,1±3,9 years; 27,3±1,4 kg/m2) performed RE in three different conditions: knee extension at 50% of one 1RM (MI), at 80% of 1RM (HI) and rest in the control group (CON). Flow mediated dilation (FMD) was assessed before, 30 and 60 minutes of exercise. Venus plasma concentration of ET-1 NOx and TBARS were measured before, immediately after and 60 minutes after exercise. Blood pressure was evaluated before and after exercise. Results. There was a significant improvement in FMD 30 minutes after exercise in the MI condition (12,5± 4,10 vs 17,2±3,9%; p= 0,016; p=0,01). The plasma NOx concentration was significant higher immediately after MI (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). There was a significant improvement in the plasma ET-1 concentration immediately after HI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). There was no significant difference in the BP between the experimental conditions (MI vs HI) and TBARS throughout the experimental conditions. Conclusions. Resistance exercise performed in moderate intensity improve endothelial function in sedentary middle aged men, there results suggest that lower intensities of RE could be safe for this population in the beginning of the exercise programs.

Introdução: Os fitoesteróis são indicados no tratamento da hipercolesterolemia. Embora sua ação sobre a redução do colesterol já tenha sido exaustivamente estudada, não se encontra bem elucidada na literatura, a forma como atua sobre biomarcadores inflamatórios e endoteliais em indivíduos hipercolesterolêmicos. Objetivo: Avaliar o efeito do fitoesterol adicionado ao leite de soja sobre as concentrações plasmáticas de lípides e biomarcadores, além de alterações em vias transcricionais envolvidos na patogênese da aterosclerose em células linfomononucleares em indivíduos moderadamente hipercolesterolêmicos. Metodologia: Foram estudados 38 pacientes, recrutados no Ambulatório do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Inicialmente, os pacientes foram submetidos a um período basal de três semanas para avaliar a aderência e tolerabilidade ao leite de soja padrão (Placebo). Foram orientados a manter os hábitos alimentares e a atividade física. Receberam 400 mL/dia de leite de soja padrão ou enriquecido com fitoesteróis (1,6 g/dia) por dois períodos de quatro semanas em que o estudo foi randomizado, cego e cruzado. Resultados: O peso corporal foi mantido durante o estudo. O tratamento com fitoesterol reduziu o colesterol total em 5,5 % (P<0,001), a lipoproteína de baixa densidade (LDL) em 6,4 % e os triglicérides em 8,3 % (P<0,05) e aumentaram as concentrações de campesterol e sitosterol no plasma em 18,9% e 21,6%, respectivamente. Não houve alteração nos valores de lipoproteína de alta densidade (HDL). Com relação aos biomarcadores de aterosclerose, os fitoesteróis provocaram redução apenas na endotelina-1 em 11 % (P<0,05). Esta ação foi independente da redução do LDL-C. Não houve alteração no RNAm para 3-hydroxy-3-methylglutaryl coenzyme A redutase e receptor de LDL. Conclusão: Os fitoesteróis são eficientes na redução da concentração plasmática do colesterol total, triglicérides, LDL-C e da endotelina-1, sendo esta última independente da redução do colesterol / Background: Phytosterols are recommended in the treatment of moderate hypercholesterolemia. Although their mechanisms of action on cholesterol reduction has been exhaustively studied, other activities, such as their effects on inflammatory arterial markers and on endothelial function, have not yet been fully investigated. Objective: To evaluate the efficacy of phytosterols added to soy milk on the reduction of plasma lipids, on biomarkers involved in the pathogenesis of atherosclerosis and on transcriptional changes in 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase and low density lipoprotein receptor in moderately hypercholesterolemic individuals. Design: Moderately hypercholesterolemic patients (n=38, mean age 58 y) were initially followed over a 3-wk baseline period to evaluate their adherence to the program and their tolerance to the added milk. Patients received soy milk (400 mL/d) or soy milk + phytosterol (1.6 g/d) for 2 periods of 4-wk each. The study was randomized, blinded and crossed. Results: Body weight was maintained during the study. Phytosterol treatment reduced the total cholesterol concentration 5.5 % (P < 0.001), low density lipoprotein (LDL) 6.4 % and triglycerides 8.3 % (P<0.05), without modifying high density lipoprotein (HDL). Phytosterol reduced plasma endothelin-1 by 11 % (P<0.05), independently of LDL-C lowering activity. No effects on LDL receptor or on HMGCoA reductase mRNA expression in mononuclear blood cells were found. Sitosterol and campesterol plasma concentrations increased with phytosterol consumption by 18.9% and 21.6%, respectively. Conclusions: Phytosterol effectively lowered plasma total cholesterol, LDL-C, triglycerides and endothelin-1 concentration. The reduction in endothelin-1 concentration was independent of the decrease in the LDL-C concentration