Honokiol ameliorates endothelial dysfunction through suppression of PTX3 expression, a key mediator of IKK/IkappaB/NF-kappaB, in atherosclerotic cell model

Pentraxin 3 (PTX3) was identified as a marker of the inflammatory response and overexpressed in various tissues and cells related to cardiovascular disease. Honokiol, an active component isolated from the Chinese medicinal herb Magnolia officinalis, was shown to have a variety of pharmacological activities. In the present study, we aimed to investigate the effects of honokiol on palmitic acid (PA)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and to elucidate potential regulatory mechanisms in this atherosclerotic cell model. Our results showed that PA significantly accelerated the expression of PTX3 in HUVECs through the IkappaB kinase (IKK)/IkappaB/nuclear factor-kappaB (NF-kappaB) pathway, reduced cell viability, induced cell apoptosis and triggered the inflammatory response. Knockdown of PTX3 supported cell growth and prevented apoptosis by blocking PA-inducted nitric oxide (NO) overproduction. Honokiol significantly suppressed the overexpression of PTX3 in PA-inducted HUVECs by inhibiting IkappaB phosphorylation and the expression of two NF-kappaB subunits (p50 and p65) in the IKK/IkappaB/NF-kappaB signaling pathway. Furthermore, honokiol reduced endothelial cell injury and apoptosis by regulating the expression of inducible NO synthase and endothelial NO synthase, as well as the generation of NO. Honokiol showed an anti-inflammatory effect in PA-inducted HUVECs by significantly inhibiting the generation of interleukin-6 (IL-6), IL-8 and monocyte chemoattractant protein-1. In summary, honokiol repaired endothelial dysfunction by suppressing PTX3 overexpression in an atherosclerotic cell model. PTX3 may be a potential therapeutic target for atherosclerosis.

Long-term use of first-line highly active antiretroviral therapy is not associated with carotid artery stiffness in human immunodeficiency virus-positive patients

Objective: To evaluate whether or not highly active antiretroviral therapy is associated with carotid artery stiffness in human immunodeficiency virus-positive patients in Henan Province, China. Method: Fifty human immunodeficiency virus-positive patients with at least a 5-year history of highly active antiretroviral therapy use and 50 human immunodeficiency virus-positive patients without a history of highly active antiretroviral therapy use were enrolled in this study. Carotid artery intima-media thickness and stiffness were determined by quantitative inter-media thickness and quantitative artery stiffness, respectively. Results: No statistically significant difference in carotid artery intima-media thickness and stiffness was observed between groups. A significant association between human immunodeficiency virus infection time and carotid artery stiffness was observed, but no significant association between human immunodeficiency virus infection time and intima-media thickness was found. No significant association between intima-media thickness, stiffness, and CD4+ and CD8+ T-cell counts were observed. Conclusion: The first-line highly active antiretroviral therapy currently used in China is not associated with carotid artery stiffness in human immunodeficiency virus-positive patients with good highly active antiretroviral therapy compliance. Human immunodeficiency virus may play a role in the development of atherosclerosis. .

Efeito da combinação de sinvastatina com paclitaxel veiculado por nanoemulsão lipídica na aterosclerose induzida em coelhos / Effect of a combination of simvastatin and paclitaxel carried by a lipid nanoemulsion on induced atherosclerosis in rabbits

Em estudos prévios, mostramos que uma nanoemulsão lipídica (LDE) é reconhecida e se liga aos receptores de LDL após sua injeção na corrente sanguínea. Como tais receptores estão superexpressos em células com altas taxas de proliferação, como ocorre no câncer e na aterosclerose, a LDE pode ser utilizada como veículo para direcionar fármacos a essas células, diminuindo sua toxicidade e aumentando sua eficácia terapêutica. Anteriormente, reportamos que o tratamento com um derivado do paclitaxel, o oleato de paclitaxel, associado à LDE (PTX-LDE), reduziu em 60% a área lesionada de aortas de coelhos submetidos à dieta aterogênica, comparados a animais não tratados. No presente trabalho, avaliamos o efeito da associação de sinvastatina, medicamento hipolipemiante, e PTX-LDE, sobre a aterosclerose induzida por dieta em coelhos. Trinta e seis coelhos machos da raça Nova Zelândia foram submetidos à dieta enriquecida com 1% de colesterol durante oito semanas. A partir da quinta semana, os animais foram divididos em quatro grupos, de acordo com o tratamento: controle (solução salina EV), sinvastatina (2mg/kg/dia, VO), paclitaxel (PTX-LDE, 4mg/Kg/semana, EV), ou combinação de sinvastatina (2mg/Kg/dia, VO) com paclitaxel (PTX-LDE, 4mg/Kg/semana, EV). Após oito semanas, os animais foram sacrificados para análise das aortas. Em comparação aos controles, a área lesionada das aortas foi em torno de 60% menor, tanto no grupo paclitaxel, quanto no grupo da combinação, e em torno de 40% menor no grupo sinvastatina (p<0,05). A razão entre as camadas íntima/média foi menor nos grupos tratados, em relação ao grupo controle (controles, 0,35±0,22, sinvastatina, 0,10±0,07, paclitaxel, 0,06±0,16 e combinação, 0,09±0,05, p<0,0001). Os grupos combinação e sinvastatina apresentaram um aumento da porcentagem de colágeno nas lesões (combinação, 20% e sinvastatina, 22%), em comparação aos controles (11%) e ao grupo paclitaxel (12%), (p<0,0001). Houve uma diminuição da porcentagem de macrófagos na lesão em todos os grupos tratados (paclitaxel, 11%, sinvastatina, 8% e combinação, 5%), comparados ao grupo controle (30%), (p<0,0001). O grupo paclitaxel apresentou menor porcentagem de células musculares lisas na lesão (20%) em relação aos controles (33%), (p<0,0001), já na combinação, houve aumento dessa porcentagem (44%), (p<0,0001). A combinação com sinvastatina não aumentou a eficácia do tratamento com PTX-LDE na redução da área de lesões ateroscleróticas, porém, os efeitos adicionais sobre o perfil lipídico e na composição das lesões, observadas com o uso da combinação, são achados importantes, que sugerem benefícios no sentido de aumentar a estabilidade das placas ateroscleróticas, o que nos abre um caminho de pesquisa muito promissor

In previous studies we have shown that a lipid nanoemulsion (LDE) is recognized and binds to LDL receptors after injection into the bloodstream. As those receptors are upregulated in cells with higher proliferation rates, as occurs in cancer and atherosclerosis, LDE can be used as a vehicle to direct drugs to those cells, diminishing toxicity and increasing therapeutic efficacy. Previously, we reported that treatment with antiproliferative agent paclitaxel derivative, paclitaxel oleate, associated with LDE (PTX-LDE), reduced by 60% the injured area of the aorta of rabbits subjected to atherogenic diet compared to untreated animals. In the current study we aim to test the effect of a combination of lipid-lowering drug simvastatin with PTX-LDE on diet-induced atherosclerosis in rabbits. Thirty-six male New Zealand rabbits were fed a 1% cholesterol diet for 8 weeks. Starting from week 5, animals were divided into four groups, according to the following treatments: controls (I.V. saline solution injections), simvastatin P.O. (2mg/kg/day), paclitaxel (PTX-LDE I.V. injections, 4mg/Kg/week), or paclitaxel-simvastatin combination (PTX-LDE I.V., 4mg/Kg/week + simvastatin P.O., 2mg/Kg/day). After 8 weeks, the animals were sacrificed for aorta evaluation. Compared to controls, the injured area was reduced by 60% in both paclitaxel and combination groups, and by 40% in simvastatin group (p<0,05). The intima/media ratio was reduced in treated groups, compared to control group (controls, 0,35±0,22, simvastatin, 0,10±0,07, paclitaxel, 0,06±0,16 and combination, 0,09±0,05, p<0,0001). Simvastatin and combination groups showed increased collagen content within the lesions (simvastatin, 22% and combination 20%), compared to controls (11%) and to paclitaxel group (12%), (p <0.0001). Macrophage content within the lesions was reduced in all treated groups (paclitaxel, 11%, simvastatin, 8% e combination, 5%), compared to controls (30%), (p <0.0001). The percentage of smooth muscle cells in the lesions was diminished in paclitaxel group (20%) compared to control group (33%), while the combination group showed increased percentage (44%) of smooth muscle cells in the lesions (p<0,0001). The combination of simvastatin did not improve the efficacy of the treatment with PTXLDE in reducing the area of atherosclerotic lesions, but the additional effects on lipid profile and lesion composition observed with the use of the combination are important findings that suggest benefits in order to enhance the stability of atherosclerotic plaques, which may lead us to a very promising research path

Tabaquismo y aterosclerosis / Smoking and aterosclerosis

Las personas subestiman el gran riesgo que produce el tabaquismo para la salud. Existen varias clasificaciones relacionadas con los factores de riesgo que este hábito implica; una de ellas lo sitúa como factor de riesgo principal junto a la hiperlipidemia, la hipertensión arterial y la diabetes mellitus; otra lo clasifica como factor de riesgo potencialmente modificable de enfermedad vascular coronaria, cerebral y periférica. Si se considera el riesgo de desarrollar una enfermedad cardiovascular de una persona del sexo masculino de 40 años en relación al tabaco, el colesterol sérico y la hipertensión arterial, la presencia simultánea de los tres factores da un riesgo tres veces mayor que la suma de los efectos individuales. El tabaquismo es una causa importante de enfermedad cerebro vascular y ésta es responsable de 57 muertes x 100,000 habitantes. El fumar aumenta la probabilidad de hemorragia subaracnoidea en fumadores y asociado a anticonceptivos orales aumenta este riesgo. La situación actual del problema del tabaquismo en Cuba es su asociación como factor de riesgo a las primeras causas de muerte prematura. Encuestas nacionales de factores de riesgo realizadas en 1995 arrojaron un 37 por ciento de prevalencia de tabaquismo.

Self-expandable nitinol stent placement in homocysteinemic porcine aorta

PURPOSE: To compare aortic intimal thickening of normal and hyperhomocysteinemic pigs (induced with a methionine-rich diet) following placement of a self-expanding nitinol stent. METHODS: Eighteen Macau pigs were used. They were older than eight weeks in age and had an average weight of 30 kg. Pigs were randomly divided into two groups. The first, Group C (control), was fed a regular diet, and the second group, Group M, was fed a methionine-rich diet for 30 days to induce hyperhomocysteinemia. The self-expandable nitinol stents were 25mm in length and 8 mm in diameter after expansion. Blood samples were collected to measure total cholesterol, triglycerides, HDL and homocysteine concentrations. All animals were subjected to angiography. Thirty days after the procedure, the animals were sacrificed, and the abdominal aorta was removed for histological and digital morphometry analysis. RESULTS: Under microscopic evaluation, the intima was significantly thicker in Group C than in Group M. When groups were compared by digital morphometric analysis, intimal thickening of the vessel wall was higher in Group C than in Group M. There was no significant change in total cholesterol, triglycerides or HDL concentrations in either group. In group C the levels of plasma homocysteine ranged from 14,40 to 16,73µmol/l; in Group M, plasma homocysteine levels ranged from 17.47 to 59.80 µmol/l after 30 days of a methionine-rich diet. CONCLUSION: Compared to normal pigs, less intimal hyperplasia was observed in the abdominal aortas of hyperhomocysteinemic pigs thirty days after the insertion of a self-expandable nitinol stent.

Estudio de ingesta y niveles séricos de cobre como factor de riesgo de enfermedad ateromatosa / Copper intake and blood levels as risk factor for atherosclerosis

Zinc and copper intake, plasma levels and serum lipid levels were measured in 20 patients with cerebrovascular disease, 20 patients with an acute myocardial infarction and 40 subjects hospitalized for elective surgery, that served as controls. Results: Copper and zinc intake was below recommended allowances in all subjects. Serum zinc and copper levels did not differ in the three study groups. In patients with myocardial infarction a weak correlation was found between serum copper and total cholesterol (r = 0.24; p < 0.05) and LDL cholesterol (r = 0.31; p < 0.05). Conclusions: No differences in copper levels were found in subjects with atherosclerosis and controls. The correlation between serum copper and cholesterol deserves further investigation

Increased prevalence of diabetes mellitus and atherosclerosis during testosterone administration in rabbits

The effects of non-physician prescribed, self-obtained and self- administered exogenous androgenic steroid testosterone on serum total cholesterol, high- and low-density lipoprotein cholesterol [HDL-C, LDL-C], triacylglycerols, glucose [fasting and after 2 hr of an oral glucose load], insulin, total testosterone and gonadotropic hormones were evaluated in rabbits. Testosterone propionate [TP] was administered to male rabbits at a dose level of 25 mg intramuscular body wt/week for 6 weeks. A statistically significant increase [P < 0.05] in serum levels of total cholesterol, triacylgycerols, LDL-C, insulin, total testosterone, glucose [after 2 hr.], body wt., as well as a significant decrease in HDL-C and gonadortopic hormones [FSH, LH] were observed in drug treated animals than in control group. These results suggest that [TP] administration at a massive dose has an increased prevalence of diabetes mellitus and atherosclerosis