Coagulation and platelet biology at the intersection of health and disease: illustrated capsules of the 11th Symposium on Hemostasis at the University of North Carolina.

The University of North Carolina Symposia on Hemostasis began in 2002, with The First Symposium on Hemostasis with a Special Focus on FVIIa and Tissue Factor. They have occurred biannually since and have maintained the primary goal of establishing a forum for the sharing of outstanding advances made in the basic sciences of hemostasis. The 2024 11th Symposium on Hemostasis will bring together leading scientists from around the globe to present and discuss the latest research related to coagulation factors and platelet biology. In keeping with the tradition of the conference, we expect novel cross-disciplinary collaborations to result from bringing together fundamental scientists and physician-scientists from different backgrounds and perspectives. The aim of these collaborations is to springboard the next generation of important advances in the field. This year's program was designed to discuss Coagulation and Platelet Biology at the Intersection of Health and Disease. The goal is to develop a better understanding of the pathophysiologic mechanisms leading to hemostatic and thrombotic disorders as this understanding is critical for the continued development of safe and efficacious therapeutics. Included in this review article are illustrated capsules provided by our speakers that highlight the main conclusions of the invited talks.

Platelet binding to polymerizing fibrin is avidity driven and requires activated αIIbß3 but not fibrin cross-linking.

The molecular basis of platelet-fibrin interactions remains poorly understood despite the predominance of fibrin in thrombi. We have studied the interaction of platelets with polymerizing fibrin by adding thrombin to washed platelets in the presence of the peptide RGDW, which inhibits the initial platelet aggregation mediated by fibrinogen binding to αIIbß3 but leaves intact a delayed increase in light transmission (delayed wave; DW) as platelets interact with the polymerizing fibrin. The DW was absent in platelets from a patient with Glanzmann thrombasthenia, indicating a requirement for αIIbß3. The DW required αIIbb3 activation and it was inhibited by the αIIbß3 antagonists eptifibatide and the monoclonal antibody (mAb) 7E3, but only at much higher concentrations than needed to inhibit platelet aggregation initiated by a thrombin receptor activating peptide (T6). Surface plasmon resonance and scanning electron microscopy studies both supported fibrin having greater avidity for αIIbß3 than fibrinogen rather than greater affinity, consistent with fibrin's multivalency. mAb 10E5, a potent inhibitor of T6-induced platelet aggregation, did not inhibit the DW, suggesting that fibrin differs from fibrinogen in its mechanism of binding. Inhibition of factor XIII-mediated fibrin cross-linking by >95% reduced the DW by only 32%. Clot retraction showed a pattern of inhibition similar to that of the DW. We conclude that activated αIIbß3 is the primary mediator of platelet-fibrin interactions leading to clot retraction, and that the interaction is avidity driven, does not require fibrin cross-linking, and is mediated by a mechanism that differs subtly from that of the interaction of αIIbß3 with fibrinogen.

Dominant role of αIIbß3 in platelet interactions with cross-linked fibrin fragment D-dimer.

Although much is known about the interaction of fibrinogen with αIIbß3, much less is known about the interaction of platelets with cross-linked fibrin. Fibrinogen residue Lys406 plays a vital role in the interaction of fibrinogen with αIIbß3, but because it participates in fibrin cross-linking, it is not available for interacting with αIIbß3. We studied the adhesion of platelets and HEK cells expressing normal and constitutively active αIIbß3 to both immobilized fibrinogen and D-dimer, a proteolytic fragment of cross-linked fibrin, as well as platelet-mediated clot retraction. Nonactivated platelets and HEK cells expressing normal αIIbß3 adhered to fibrinogen but not D-dimer, whereas activated platelets as well as HEK cells expressing activated αIIbß3 both bound to D-dimer. Small-molecule antagonists of the αIIbß3 RGD (Arg-Gly-Asp) binding pocket inhibited adhesion to D-dimer, and an Asp119Ala mutation that disrupts the ß3 metal ion-dependent adhesion site inhibited αIIbß3-mediated adhesion to D-dimer. D-dimer and a polyclonal antibody against D-dimer inhibited clot retraction. The monoclonal antibody (mAb) 10E5, directed at αIIb and a potent inhibitor of platelet interactions with fibrinogen, did not inhibit the interaction of activated platelets with D-dimer or clot retraction, whereas the mAb 7E3, directed at ß3, inhibited both phenomena. We conclude that activated, but not nonactivated, αIIbß3 mediates interactions between platelets and D-dimer, and by extrapolation, to cross-linked fibrin. Although the interaction of αIIbß3 with D-dimer differs from that with fibrinogen, it probably involves contributions from regions on ß3 that are close to, or that are affected by, changes in the RGD binding pocket.

Novel Pure αVß3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations.

The integrin αVß3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVß3-mediated cell adhesion to αVß3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the αVß3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitide's enhancement of tumor growth in vivo.

ABC transporters in megakaryopoiesis and platelet activity.

ATP-binding cassette (ABC) is a family of transporters that facilitates the translocation of substrates across cell membrane using its ATPase subunit. These transporters have key roles in multidrug resistance, lipid homeostasis, antigen processing, immunity, cell proliferation and hematopoiesis. Some ABC transporters are selectively expressed on megakaryocyte progenitor, megakaryocyte and its cellular fragment platelet. However, the role of ABC transporters in hemostasis and thrombosis were not well explored until recently. Studies of both human genetic diseases and genetically-manipulated animal models have greatly improved our understanding of ABC transporters in regulating hematopoiesis particularly megakaryopoiesis and/or platelet activity. Human genome wide association studies (GWAS) have also unraveled the association between ABC transporters and thrombopoiesis in general population. Therefore, this review aims to summarize the recent advances in our understanding of how ABC transporters regulate megakaryopoiesis and platelet activity, the underlining mechanisms and their association with atherosclerosis and atherothrombosis. Last, the emerging therapeutic targets to slow down atherosclerosis development and prevent atherothrombosis via ABC transporters or downstream pathways will also be discussed.

αIIbß3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia.

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbß3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbß3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and ß3 C547G severely reduced αIIbß3 expression, whereas αIIb P943A partially reduced αIIbß3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69-98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or ß3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbß3 and highlight the challenges in predicting the clinical significance of novel missense variants.

Tyrosine phosphorylation on spleen tyrosine kinase (Syk) is differentially regulated in human and murine platelets by protein kinase C isoforms.

Protein kinase C (PKC) isoforms differentially regulate platelet functional responses downstream of glycoprotein VI (GPVI) signaling, but the role of PKCs regulating upstream effectors such as Syk is not known. We investigated the role of PKC on Syk tyrosine phosphorylation using the pan-PKC inhibitor GF109203X (GFX). GPVI-mediated phosphorylation on Syk Tyr-323, Tyr-352, and Tyr-525/526 was rapidly dephosphorylated, but GFX treatment inhibited this dephosphorylation on Tyr-525/526 in human platelets but not in wild type murine platelets. GFX treatment did not affect tyrosine phosphorylation on FcRγ chain or Src family kinases. Phosphorylation of Lat Tyr-191 and PLCγ2 Tyr-759 was also increased upon treatment with GFX. We evaluated whether secreted ADP is required for such dephosphorylation. Exogenous addition of ADP to GFX-treated platelets did not affect tyrosine phosphorylation on Syk. FcγRIIA- or CLEC-2-mediated Syk tyrosine phosphorylation was also potentiated with GFX in human platelets. Because potentiation of Syk phosphorylation is not observed in murine platelets, PKC-deficient mice cannot be used to identify the PKC isoform regulating Syk phosphorylation. We therefore used selective inhibitors of PKC isoforms. Only PKCß inhibition resulted in Syk hyperphosphorylation similar to that in platelets treated with GFX. This result indicates that PKCß is the isoform responsible for Syk negative regulation in human platelets. In conclusion, we have elucidated a novel pathway of Syk regulation by PKCß in human platelets.

Dextran sulphate induces fibrinogen receptor activation through a novel Syk-independent PI-3 kinase-mediated tyrosine kinase pathway in platelets.

In our attempt to find a physiological agonist that activates PAR3 receptors, we screened several coagulation proteases using PAR4 null platelets. We observed that FXIIa and heat inactivated FXIIa, but not FXII, caused platelet aggregation. We have identified a contaminant activating factor in FXIIa preparation as dextran sulfate (DxS), which caused aggregation of both human and mouse platelets. DxS-induced platelet aggregation was unaffected by YM254890, a Gq inhibitor, but abolished by pan-Src family kinase (SFK) inhibitor PP2, suggesting a role for SFKs in this pathway. However, DxS-induced platelet aggregation was unaffected in FcRγ-chain null murine platelets, ruling out the possibility of glycoprotein VI-mediated events. More interesting, OXSI-2 and Go6976, two structurally unrelated inhibitors shown to affect Syk, had only a partial effect on DxS-induced PAC-1 binding. DxS-induced platelet aggregation and intracellular calcium increases were abolished by the pan PI-3 kinase inhibitor LY294002, or an isoform-specific PI-3 kinase ß inhibitor TGX-221. Pretreatment of platelets with Syk inhibitors or ADP receptor antagonists had little effect on Akt phosphorylation following DxS stimulation. These results, for the first time, establish a novel tyrosine kinase pathway in platelets that causes fibrinogen receptor activation in a PI-3 kinase-dependent manner without a crucial role for Syk.

Cbl proteins in platelet activation.

Platelets play a fundamental role in hemostasis. Their functional responses have to be tightly controlled as any disturbance may lead to bleeding disorders or thrombosis. It is thus important to clearly identify and understand the signaling mechanisms involved in platelet function. An important role of c-Cbl and Cbl-b ubiquitin ligases in platelet functional responses and in hematological malignancies has been recently described. Cbl proteins perform negative and positive regulation of several signaling pathways in platelets. In this review, we explore the role of Cbl proteins in platelet functional responses.

Tyrosine phosphorylated c-Cbl regulates platelet functional responses mediated by outside-in signaling.

c-Cbl protein functions as an E3 ligase and scaffolding protein, where 3 residues, Y700, Y731, and Y774, upon phosphorylation, have been shown to initiate several signaling cascades. In this study, we investigated the role of these phospho-tyrosine residues in the platelet functional responses after integrin engagement. We observed that c-Cbl Y700, Y731 and Y774 undergo phosphorylation upon platelet adhesion to immobilized fibrinogen, which was inhibited in the presence of PP2, a pan-src family kinase (SFK) inhibitor, suggesting that c-Cbl is phosphorylated downstream of SFKs. However, OXSI-2, a Syk inhibitor, significantly reduced c-Cbl phosphorylation at residues Y774 and Y700, without affecting Y731 phosphorylation. Interestingly, PP2 inhibited both platelet-spreading on fibrinogen as well as clot retraction, whereas OXSI-2 blocked only platelet-spreading, suggesting a differential role of these tyrosine residues. The physiologic role of c-Cbl and Y731 was studied using platelets from c-Cbl KO and c-Cbl(YF/YF) knock-in mice. c-Cbl KO and c-Cbl(YF/YF) platelets had a significantly reduced spreading over immobilized fibrinogen. Furthermore, clot retraction with c-Cbl KO and c-Cbl(YF/YF) platelets was drastically delayed. These results indicate that c-Cbl and particularly its phosphorylated residue Y731 plays an important role in platelet outside-in signaling contributing to platelet-spreading and clot retraction.

Aerobic exercise during pregnancy improves health-related quality of life: a randomised trial.

QUESTION: Does supervised aerobic exercise during pregnancy improve health-related quality of life in nulliparous women? DESIGN: Analysis of secondary outcomes of a randomised trial with concealed allocation, blinded assessors, and intention-to-treat analysis. PARTICIPANTS: 64 nulliparous, pregnant women attending for prenatal care at one of three tertiary hospitals. INTERVENTION: The experimental group completed a 3-month supervised exercise program, commencing at 16 to 20 weeks of gestation. Each session included walking (10 min), aerobic exercise (30 min), stretching (10 min), and relaxation (10 min). The control group continued usual activities and performed no specific exercise. OUTCOME MEASURES: The primary outcome was health-related quality of life assessed by the Colombian version of the Medical Outcome Study Short-Form Health Survey at baseline and immediately after the 3-month intervention. RESULTS: Fifty women completed the study. After the 3-month intervention, the experimental group had improved their health-related quality of life more than the control group in the physical component summary of the questionnaire by 6 points (95% CI 2 to 11), the physical function domain (7 points, 95% CI 0 to 14), the bodily pain domain (7 points, 95% CI 1 to 13) and the general health domain (5 points, 95% CI 1 to 10). CONCLUSIONS: A supervised 3-month program of primarily aerobic exercise during pregnancy improves health-related quality of life. TRIAL REGISTRATION: NCT00741312.

Cbl-b is a novel physiologic regulator of glycoprotein VI-dependent platelet activation.

Cbl-b, a member of the Cbl family of E3 ubiquitin ligases, plays an important role in the activation of lymphocytes. However, its function in platelets remains unknown. We show that Cbl-b is expressed in human platelets along with c-Cbl, but in contrast to c-Cbl, it is not tyrosine-phosphorylated upon glycoprotein VI (GPVI) stimulation. Cbl-b, unlike c-Cbl, is not required for Syk ubiquitylation downstream of GPVI activation. Phospholipase Cgamma2 (PLCgamma2) and Bruton's tyrosine kinase (BTK) are constituently associated with Cbl-b. Cbl-b-deficient (Cbl-b(-/-)) platelets display an inhibition in the concentration-response curve for GPVI-specific agonist-induced aggregation, secretion, and Ca(2+) mobilization. A parallel inhibition is found for activation of PLCgamma2 and BTK. However, Syk activation is not affected by the absence of Cbl-b, indicating that Cbl-b acts downstream of Syk but upstream of BTK and PLCgamma2. When Cbl-b(-/-) mice were tested in the ferric chloride thrombosis model, occlusion time was increased and clot stability was reduced compared with wild type controls. These data indicate that Cbl-b plays a positive modulatory role in GPVI-dependent platelet signaling, which translates to an important regulatory role in hemostasis and thrombosis in vivo.

[In vitro effect of caffeine on internal mammary artery rings used in cardiac revascularization surgery]. / Acción in vitro de la cafeína en anillos de arteria mamaria interna utilizada en cirugía de revascularización cardiaca.

INTRODUCTION: The vasodilator effect of caffeine in animal models arteries has been demonstrated previously. However, studies with the same methodology using human arteries in vitro have not been performed. OBJECTIVES: The in vitro vasoactive effects of caffeine was evaluated on human internal mammary arteries. MATERIALS AND METHODS: Internal mammary artery rings were used (n = 20). Endothelial function was evaluated with acetylcholine at a concentration of 3.16 x 10 -6 M, nitroglycerine at cumulative concentrations of 10 -11 M to 10 -4 M and caffeine with cumulative concentrations of 10 -8 M to 10 -4 M. RESULTS: Nitroglycerin produced a maximum relaxation percentage of 87.4 +/- 12.3%, caffeine a percentage of 86.9 +/- 21.0% in arteries with functional endothelium, and of 71.6 +/- 28.6% in arteries with endothelial dysfunction. No differences were detected among the three groups ( p=0.289). Similarly, no differences were found between EC 50 in arteries with functional endothelium (1.66 x 10 -5 +/-1.57 x 10 -5 M) and dysfunctional arteries (7.8 x 10 -5 +/-14.6 x 10 -5 M). Nitroglycerine proved more potent than caffeine (EC 50 = 4.3 x 10 -9 +/-4.4 x 10 -9 M) ( p=0.013). CONCLUSIONS: Although nitroglycerin was a more potent vasodilator, caffeine had a strong arterial vasodilator effect regardless of endothelial function in human arteries.

Acción in vitro de la cafeína en anillos de arteria mamaria interna utilizada en cirugía de revascularización cardiaca / In vitro effect of caffeine on internal mammary artery rings used in cardiac revascularization surgery

Introducción. El efecto vasodilatador de la cafeína en las arterias de modelos animales ya ha sido demostrado. Se desconocen estudios con la misma metodología in vitro utilizando arterias humanas. Objetivos. Evaluar los efectos vasoactivos in vitro de la cafeína en la arteria mamaria interna de humanos. Materiales y métodos. Se utilizaron 80 anillos de arteria mamaria interna (n=20 pacientes). La funcionalidad del endotelio se evaluó con acetilcolina a una concentración de 3,16x10 -6 M, de nitroglicerina con dosis acumulativas de 10 –11 M a 10 –4 M y de cafeína con concentraciones acumulativas de 10 –8 M a 10 –4 M. Resultados. La nitroglicerina indujo un porcentaje máximo de relajación de 87,4±12,3 por ciento, la cafeína, de 86,9±21,0 por ciento en arterias con endotelio funcional y de 71,6±28,6 por ciento en arterias con disfunción endotelial. No se encontraron diferencias entre los tres grupos ( p=0,289). Tampoco se encontraron diferencias en la EC 50 en arterias con endotelio funcional (1,66x10 -5 ±1,57x10 -5 M) y arterias disfuncionales (7,75x10 -5 ±14,64x10 -5 M). La nitroglicerina resultó más potente que la cafeína (EC 50 = 4,30x10 -9 ±4,35x10 -9 M) ( p=0,013). Conclusiones. Aunque la nitroglicerina fue un vasodilatador más potente, la cafeína tuvo un fuerte efecto vasodilatador arterial in vitro independientemente de la funcionalidad del endotelio en arterias humanas.

Micro-organismos efectivos (EM-X): acción in-vivo sobre aorta de conejos hipercolesterolémicos / Effective microorganisms (EM-X): in-vitro action on aorta of hypercholesterolemic rabbits

Antecedentes y objetivos: EM-X es una bebida antioxidante derivada del salvado de arroz y extractos de algas marinas fermentadas con micro-organismos efectivos. El objetivo de este estudio fue determinar si el EM-X previene la formación de placa aterosclerótica y favorece la relajación vascular in-vitro en un modelo de aterosclerosis temprana en conejos hipercolesterolémicos.Métodos: la población se dividió en cuatro grupos: 1: conejos ateroscleróticos con administración de EM-X; 2: conejos ateroscleróticos sin administración de EM-X; 3: conejos sanos sin administración de EM-X; y 4: conejos sanos con administración de EM-X. A cada conejo se le midió el colesterol sérico y se le extrajeron anillos aórticos para análisis in-vitro de la relajación vascular dependiente e independiente de endotelio. Se realizaron análisis histomorfométricos y cuantificación de la endotelización arterial.

Background: EM-X is an antioxidant beverage obtained from rice bran and seaweed extracts fermented with Effective Microorganisms. The purpose of this study was to determine if EM-X prevents atherosclerotic plaque formation and favours in vitro vascular relaxation in a model of early atherosclerosis in hypercholesterolemic rabbits. Methods: The study population was divided in four groups: 1. atherosclerotic rabbits administered with EM-X, 2: atherosclerotic rabbits not administered with EM-X; 3: healthy rabbits not administered with EM-X; and 4: healthy rabbits administered with EM-X. Serum cholesterol was measured in each rabbit and vascular rings were obtained for conducting the endothelium dependent relaxation (EDR) in vitro analysis. Additionally, hystomorphometrical analysis and endothelial cell quantification were performed. Results: Whole cholesterol measurements differed significantly in groups 1 vs. 2 and 3 vs. 4 (p>0.05). EDR did not differ significantly between groups 1 and 2 (p = 0.181), or between groups 3 and 4 (p = 0.349). Hystomorphometrical characteristics did not show significant differences neither in groups 1 and 2 (p=0.85) nor in groups 3 and 4 (p=0.95). The immunohystochemical analysis did not show significant differences between any groups (p=0.85). Conclusion: The results found do not demonstrate the benefits of EM-X as antioxidant therapy in the prevention of atherosclerotic plaque formation and in vitro endothelium dependent vascular relaxation in healthy animals or with endothelial dysfunction and atherosclerosis.

The vasodilatory effects of levosimendan on the human internal mammary artery.

BACKGROUND: Levosimendan, an inotropic drug that enhances myocardial contractility through myofilment calcium sensitazion, induces peripheral vasodilation via opening ATP-dependent K(+) channels. It is unknown whether this drug can be used for the treatment of perioperative vasospasm of arterial conduits used for coronary artery bypass grafting. METHODS: We investigated the effects of levosimendan on human internal mammary artery (IMA) specimens taken from patients undergoing coronary artery bypass surgery. The rings were carefully prepared and placed between two wire hooks in organ bath chambers and then constricted submaximally with norepinephrine and thromboxane A(2) analog (U46619). Nitroglycerin, milrinone, and levosimendan were separately added in a cumulative fashion and concentration response curves for relaxation were constructed. In parallel experiments, the response to levosimendan was evaluated on rings with and without functional endothelium. Levosimendan prevention of norepinephrine-induced contraction was also estimated. RESULTS: Nitroglycerin, milrinone, and levosimendan completely reversed the contraction of the IMA segments induced by U46619 and norepinephrine. Levosimendan produced a potent, concentration-dependent preventive effect on the norepinephrine-induced contraction of IMA. The responses to levosimendan were similar in preparations with or without endothelium.

Detección de Chlamydia pneumoniae en tejido aórtico humano: amplificación del gen kdtA e hibridación in vitro / Detection of Chlamydia pneumoniae in human aortic tissue: kdtA gene amplification and in vitro hybridization

Introducción. La ateroesclerosis es la principal causa de enfermedad coronaria y cerebrovascular, las cuales, a su vez, son las causas más comunes de mortalidad y morbilidad n el mundo occidental. Publicaciones recientes sugieren que ciertos microorganismos infecciosos podrían jugar un papel importante en la génesis y progresión de la aterosclerosis. De acuerdo con reportes seroepidemiológicos y de detección directa, Chlamydia pneumoniae podría ser el candidato más plausible. No obstante, no se ha determinado su papel específico en el proceso aterogénico, por lo cual en los últimos años ha surgido la necesidad de explorar diversas técnicas de detección de C. pneumoniae en arterias. Objetivo. El propósito de este estudio fue investigar la presencia de C. pneumoniae en muestras de tejido aórtico de catorce pacientes sometidos a cirugía de reemplazo aórtico, utilizando la amplificación del gen kdtA por PCR acoplada a un ensayo de hibridación in vitro. Materiales y métodos. De cada uno de catorce segmentos de aorta se obtuvo una muestra al azar para la extracción de ADN y la detección de C. pneumoniae por PCR-hibridación in vitro. Resultados. Doce (85,7 por ciento) de catorce muestras de tejido de aorta resultaron positivas para C. pneumoniae. Conclusión. Los resultados encontrados en este estudio sugieren que la presencia de C. pneumoniae es frecuente en el tipo de muestras analizado. En estudios posteriores resultaría importante examinar si esta proporción se mantiene en una muestra poblacional mayor

Efectos pleiotrópicos de las estatinas. Características farmacológicas útiles en la prevención, tratamiento y regresión de la enfermedad cardiovascular / Pleiotropic effect of statins. Useful pharmacological characteristics in prevention, treatment and regression of cardiovascular disease

Los resultados benéficos de las estatinas en el manejo de la hipercolesterolemia en los múltiples estudios clínicos, han demostrado, además, efectos no relacionados con la acción hipolipemiante. Estudios experimentales in-vitro y ex-vivo han documentado una gran evidencia de efectos tales como incremento en la expresión de óxido nítrico y efectos anti-inflamatorios, inmunomodulatorios, anti-trombóticos, anti-proliferativos y anti-oxidantes los cuales reciben el nombre de pleiotrópicos. Los potentes efectos hipolipemiantes y pleiotrópicos podrían explicar los beneficios en aterosclerosis, hipertensión arterial, diabetes mellitus, estenosis aórtica, psoriasis, esclerosis múltiple y rechazo post-transplante entre otras patologías. Sin embargo, la cantidad de información experimental a favor de estos efectos, debería estimular a la iniciación de mejores estudios para clarificar de una manera mayor el significado clínico.

Disfunción edoltelial inducida por hipercolesterolemia: esudio in vitroen un modelo animal / Endothelial dysfunction induced by hypercholesterolemia: in vitro study ina animal model

Los factores de riesgo tradicionales como hipercolesterolemia afectan la producción endotelial o acción de sustancias vasoactivas fundamentales como el óxido nítrico (NO). Este fenómeno tiene efectos proa terogénicos y protombóricos. El objetivo del presente estudio fue evaluar los efectos in vitro de la hipercolesterolemia sobre la función endotelial y la formación de placa ateroesclerótica en tejido aórtico proveniente de conejos hipercolesterolémicos.Los resultados encontrados sugieren que los niveles elevados de colesterol sérico producen una alteración en la vasodilatación arterial dependiente de endotelio funcional, la cual se presenta sin cambios morfológicos de las células endoteliales. Se corrobora que la hipercolesterolemia es un factor de riesgo independiente de ateroesclerosis el cual contribuye a la disfunción como evento inicial en la génesis del proceso