Reacciones de N-homocisteinilación asociadas a hiperhomocisteinemia / N-homocysteinylation reactions related to hyperhomocysteinemia / Reações de N-homocisteinilação associadas a hiper-homocisteinemia

Numerosas evidencias clínicas avalan la asociación entre concentración plasmática elevada de homocisteína (hiperhomocisteinemia) y las enfermedades vasculares oclusivas, tales como la aterosclerosis y la trombosis. La homocisteína reducida (Hcy) y su éster cíclico homocisteína-tiolactona (HTL) serían los principales responsables de los efectos nocivos asociados a la hiperhomocisteinemia. Tanto la Hcy como la HTL pueden interactuar espontáneamente con proteínas, a través de reacciones de S y N-homocisteinilación, respectivamente. Ambos procesos provocan alteraciones proteicas post-traduccionales, e inducen cambios estructurales y funcionales a nivel molecular. En los últimos años ha cobrado interés el conocimiento acerca de la HTL y las consecuencias de concentraciones elevadas de este metabolito sobre la salud humana. En las reacciones de N-homocisteinilación, el grupo carbonilo de la HTL se une al grupo ε-amino de los residuos lisina de las proteínas, con lo que se generan grupos sulfhidrilo libres, susceptibles de participar en reacciones redox. Las proteínas N-homocisteiniladas pueden sufrir plegamiento incorrecto de la molécula y daño oxidativo, y en consecuencia se inducen efectos citotóxicos e inmunogénicos. Se ha establecido que la conversión metabólica de la Hcy en HTL y la N-homocisteinilación de proteínas es uno de los mecanismos involucrados en el desarrollo de patologías asociadas con la hiperhomocisteinemia, tales como las enfermedades cardiovasculares y neurodegenerativas.

Increased plasma homocysteine levels (hyperhomocysteinemia) are associated with occlusive vascular diseases, such as atherosclerosis and thrombosis. Reduced homocysteine (Hcy) and its cyclic ester, homocysteine thiolactone (HTL) would be involved in the detrimental effects associated to hyperhomocysteinemia. These two species, Hcy and HTL can spontaneously react with proteins, through S and N-homocysteinylation process, respectively. Both reactions produce post-translational protein changes, impairing structural and functional features. In recent years, interest has been developed in HTL and its effects on human health. N-homocysteinylation is the reaction between the carboxyl group of HTL and ε-amino group of lysine residues, rendering free sulfhydryl groups able to participate in redox reactions. N-homocysteinylated proteins are prone to misfolding and oxidative damage, inducing cytotoxic and immunogenic effects. Metabolic conversion of Hcy to HTL as well as protein N-homocysteinylation is one of the mechanisms underlying the development of pathologies associated to hyperhomocysteinemia, such as cardiovascular and neurodegenerative diseases.

Numerosas evidências clínicas garantem a associação entre concentração plasmática elevada de homocisteína (hiper-homocisteinemia) e as doenças vasculares oclusivas, tais como a aterosclerose e a trombose. A homocisteína reduzida (Hcy) e seu éster cíclico homocisteína tiolactona (HTL) seriam os principais responsáveis pelos efeitos nocivos associados à hiper-homocisteinemia. Tanto a Hcy quanto a HTL podem interagir espontaneamente com proteínas, através de reações de S e N-homocisteinilação, respectivamente. Ambos os processos provocam alterações proteicas pós-traducionais, induzindo alterações estruturais e funcionais em nível molecular. Nos últimos anos, cobrou interesse o conhecimento acerca da HTL e as consequências de concentrações elevadas deste metabólito sobre a saúde humana. Nas reações de N-homocisteinilação, o grupo carbonila da HTL se une ao grupo ε-amino dos resíduos lisina das proteínas, gerando grupos sulfidrila livres, suscetíveis de participar em reações redox. As proteínas N-homocisteiniladas podem sofrer dobramento incorreto da molécula e dano oxidativo, induzindo efeitos citotóxicos e imunogênicos. Estabeleceu-se que a conversão metabólica da Hcy em HTL e a N-homocisteinilação de proteínas é um dos mecanismos envolvidos no desenvolvimento de patologias associadas com a hiper-homocisteinemia, tais como as doenças cardiovasculares e neurodegenerativas.

Homocysteine in occlusive vascular disease: A risk marker or risk factor.

Homocysteine has emerged as a significant marker for occlusive vascular disease, but there has been some debate as to whether it is just an association (risk marker) or actually a causative factor (risk factor). To elucidate this, a retrospective statistical analysis was done of data generated in the course of our study on homocysteine and vascular disease. Homocysteine, lipid profile components and lipoprotein(a) were estimated in fasting blood samples drawn from 252 controls and 536 patients of occlusive vascular disease. The data were analyzed by SPSS version 17. Mean homocysteine levels were significantly higher (p<0.001) in all patients categories, as compared to controls. In fact, homocysteine level was the most significant biochemical risk factor for vascular disease. The odds ratios due to hyperhomocysteinemia varied from 3.170-4.153. When the cut-off was increased by 5 µmol/L, the odds ratio became almost three-fold. The prevalence of hyperhomocysteinemia increased by @20%, when the cut-off was reduced by 5 µmol/L. Statistical analysis of our data revealed that homocysteine conformed to Hill’s criteria of causation. Moreover, hyperhomocysteinemia was treatable by the administration of B-vitamins, even if the cause was genetic. Hence morbidity due to vascular disease could be reduced by identification and treatment of hyperhomocysteinemia.

Interventional Radiology for Vascular Diseases

Recently interventional radiologic procedures for vascular occlusive diseases have become an alternative to the surgical method. Percutaneous transluminal angioplasty(PTA) is an effective treatment for a short, concentric, segmental, stenotic lesion. The patency rate of PTA depends on the nature of the lesion. The long-term patency rate is high in iliac artery lesions. Percutaneous stent placement is an effective long-term treatment for patients with iliac insufficiency. New stents, such as a drug-coated, radioactive stent, are under investigation to overcome the re-stenosis after PTA or stent insertion. Percutaneously placed endoluminal stent-grafts for treatment of abdominal aortic aneurysm were developed to avoid major intraabdominal surgery and related morbidity and mortality.

Improvement of Cerebrovascular Reserve Capacity by Bypass Surgery in Patients with Hemodynamic Cerebral Ischemia

To study the effect of extracranial-intracranial(EC/IC) bypass on symptomatic patients with hemodynamic cerebral ischemia, we prospectively reviewed 14 patients who underwent EC/IC bypass surgery. A series of 14 patients treated in a 2 years period met the following criteria, 1) symptomatic internal carotid artery(ICA) or middle cerebral aetery(MCA) obstruction or stenosis over 80M, 2) decrease in basal cerebral blood flow(CBF) over 10%, 3) hyporeactivity to acetazolimide of CBF Amomg these, the type of ischemic episode was transient ischemic attack(TIA) or reversible ischemic neurological deficit(RIND) in 4, minor stroke in 8, and major stroke in 2. Of these, 10 patients had multiple episode of ischemic attack. CT or MRI were showed infarction of the MCA territory in 3, border zone infarction in 5, basal ganglia infarction in 2 and multiple lacunar infarction in 4. Based on our criteria, superficial temporal artery(STA)-MCA anastomosis was performed in 13 cases and EC-IC bypass grafting using radial artery in one. Average follow up period was 24 months. Postoperative course was uneventful in 12 patients. One patient suffered a postoperative stroke with complete recovery and another suffered operative wound infection. Of the 14 patients 12(85.7 % ) have had an excellent to good outcome with complete resolution or significant improvement of preoperative neurologic symptom, remaining two show no improvement of preoperative neurologic deficit. Bypass patency was confirmed by postoperative angiography in all cases except for one. Postoperative follow up studies of the basal CBF and response to the acetazolamide of the CBF showed significant increased CBF activity to acetazolamide in 12 cases(85. 7%) while the basal CBF was essentially unchanged in all cases except for two. In view of these finding, the authors suggest that EC-IC bypass surgery to be considered as an appropritate therapy for improvement of the cerebrovascular reserve capacity in patients with hemodynamic cerebral ischemia, defined using the strict selection criteria employed in this study.