Ginkgo biloba extracts prevent aortic rupture in angiotensin II-infused hypercholesterolemic mice.

Abdominal aortic aneurysms (AAAs) are a chronic vascular disease characterized by pathological luminal dilation. Aortic rupture is the fatal consequence of AAAs. Ginkgo biloba extracts (GBEs), a natural herb extract widely used as food supplements, drugs, and cosmetics, has been reported to suppress development of calcium chloride-induced AAAs in mice. Calcium chloride-induced AAAs do not rupture, while angiotensin II (AngII)-induced AAAs in mice have high rate of aortic rupture, implicating potentially different mechanisms from calcium chloride-induced AAAs. This study aimed to determine whether GBE would improve aortic dilation and rupture rate of AngII-induced AAAs. Male apolipoprotein E (apoE) -/- mice were infused with AngII and administered either GBE or its major active ingredients, flavonoids and ginkgolides, individually or in combination. To determine the effects of GBE in mice with established AAAs, male apoE-/- mice were firstly infused with AngII for 28 days to develop AAAs, and then administered either GBE or vehicle in mice with established AAAs, which were continuously infused with AngII for another 56 days. GBE, but not the two major active components separately or synergistically, prevented aortic rupture, but not aortic dilation. The protection of GBE from aortic rupture was independent of systolic blood pressure, lipid, and inflammation. GBE also did not attenuate either aortic rupture or progressive aortic dilation in mice with established AAAs. GBE did not reduce the atherosclerotic lesion areas, either. In conclusion, GBE prevents aortic rupture in AngII-infused hypercholesterolemic mice, but only in the early phase of the disease development.

Drug Therapy for Abdominal Aortic Aneurysms Utilizing Omega-3 Unsaturated Fatty Acids and Their Derivatives.

BACKGROUND: Abdominal aortic aneurysms (AAA) are life-threatening because of the potential for rupture, resulting in death. The current standard treatment for AAA is surgery, comprising laparotomic graft replacement and endovascular repair. However, because surgery carries the risk of major complications and re-intervention, drug therapies are desirable because they may reduce the occurrence of enlargement and rupture. OBJECTIVE: Recent research shows that the progression of AAA is related to inflammatory reactions, especially those in the NF-κB pathway. Omega-3 polyunsaturated fatty acids (PUFA) show antiinflammatory effects. Some derivatives of omega-3 PUFA are known as specialized pro-resolving lipid mediators (SPM) such as resolvins. They play an important role in resolving inflammation. CONCLUSION: Omega-3 PUFA and SPM may show promised effects for drug treatment of AAA.

Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies.

Aneurysms are common in the abdominal and thoracic regions of the aorta. While generally asymptomatic, progression of aneurysms is associated with the devastating consequences of aortic rupture. Current therapeutic options to prevent rupture are restricted to surgical repair, as there remains a lack of validated pharmaceutical approaches. Absence of proven medical therapies may be a consequence of the paucity of knowledge on mechanisms of aneurysmal initiation, progression and rupture. Many potential therapeutic targets have been identified in several widely used animal models of these diseases. A small number of these targets are currently under clinical evaluation, while many more are in preclinical stages of evaluation. The purpose of this review is to: (1) overview current understanding of mechanisms of aneurysmal initiation and progression and (2) summarise medical therapies that have been investigated clinically, as well as highlight future therapeutic targets.

Prostaglandin receptor EP4 in abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) pathogenesis is distinguished by vessel wall inflammation. Cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1, key components of the most well-characterized inflammatory prostaglandin pathway, contribute to AAA development in the 28-day angiotensin II infusion model in mice. In this study, we used this model to examine the role of the prostaglandin E receptor subtype 4 (EP4) and genetic knockdown of COX-2 expression (70% to 90%) in AAA pathogenesis. The administration of the prostaglandin receptor EP4 antagonist AE3-208 (10 mg/kg per day) to apolipoprotein E (apoE)-deficient mice led to active drug plasma concentrations and reduced AAA incidence and severity compared with control apoE-deficient mice (P < 0.01), whereas COX-2 genetic knockdown/apoE-deficient mice displayed only a minor, nonsignificant decrease in incidence of AAA. EP4 receptor protein was present in human and mouse AAA, as observed by using Western blot analysis. Aortas from AE3-208-treated mice displayed evidence of a reduced inflammatory phenotype compared with controls. Atherosclerotic lesion size at the aortic root was similar between all groups. In conclusion, the prostaglandin E(2)-EP4 signaling pathway plays a role in the AAA inflammatory process. Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of AAA in the angiotensin II mouse model, potentially via attenuation of cytokine/chemokine synthesis and the reduction of matrix metalloproteinase activities.

Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques: a comparison with a high-dose simvastatin therapy.

This study was carried out to test the hypothesis that Tongxinluo (TXL) as a Chinese herbal medicine enhances stability of vulnerable plaque dose dependently via lipid-lowering and anti-inflammation effects, similar to a high-dose simvastatin therapy. After abdominal aortic balloon injury, 75 rabbits were fed a 1% cholesterol diet for 10 wk and were then divided into five groups for 8-wk treatment: control group, low-dose TXL group, moderate-dose TXL group, high-dose TXL group, and high-dose simvastatin group. At the end of week 16, an adenovirus containing p53 was injected into the abdominal aortic plaques. Two weeks later, plaque rupture was induced by pharmacological triggering. The incidence of plaque rupture in all treatment groups (14.3%, 7.1%, 7.7%, and 7.1%) was significantly lower than that in control group (73.3%; P>0.01). TXL dose-dependently lowered serum lipid levels and inhibited systemic inflammation. Corrected acoustic intensity and fibrous cap thickness of the aortic plaques were significantly increased, whereas plaque area, plaque burden, vulnerable index, and expression of oxidized low-density lipoprotein (ox-LDL) receptor 1, matrix metalloproteinase 1 (MMP-1), MMP-3, tissue inhibitor of MMP 1, and NF-kappaB in plaques were markedly reduced in all treatment groups when compared with the control group. Similar to high-dose simvastatin group, high-dose TXL group exhibited a low serum level of low-density lipoprotein cholesterol and ox-LDL, a low expression level of systemic and local inflammatory factors and a low plaque vulnerability index, with no differences in the incidence of plaque rupture among all treatment groups. TXL dose-dependently enhances the stability of vulnerable plaques and prevents plaques from rupture. Simvastatin and TXL offer similar protection in terms of lipid-lowering, anti-inflammation, and antioxidation effects.

Aqueous extract of rhubarb stabilizes vulnerable atherosclerotic plaques due to depression of inflammation and lipid accumulation.

The study evaluated the effect of the traditional Chinese medicine rhubarb on the stability of atherosclerotic plaque. Atherosclerotic lesions were induced in rabbits through balloon injury with a high-cholesterol diet and then were divided into a control group, a rhubarb group and a simvastatin group. At week 24 recombinant-p53 adenoviruses were locally delivered to the atherosclerotic plaques. At week 26 plaque rupture was triggered by the intra-arterial Chinese Russell's viper venom and histamine. Serological, ultrasonographic, pathologic, immunohistochemical and gene expression studies were performed. The results showed that the incidence of plaque rupture in the rhubarb group and the simvastatin group was significantly lower than that in the control group (42.86% and 35.71% versus 80.00%, both p < 0.05). Serum TC, LDL-C (p < 0.05-0.01), IMT (both p < 0.01), PA (both p < 0.01), PB (%) (both p < 0.01) and the mRNA and protein expressions of TLR2, TLR4 and NF-kappaB (p < 0.05, 0.01, respectively) in the rhubarb group and the simvastatin group were significantly lower than those in the control group. In contrast, AIIc% (both p < 0.05) in the two treatment groups were significantly higher than those in the control group. These results suggest that rhubarb has antiatherosclerotic and plaque-stabilizing properties due to antiinflammation and lipid-lowering effects.

Screening for abdominal aortic aneurysms.

Ruptured aneurysm of the abdominal aorta is a common preventable cause of death, accounting for 2% of all deaths in men over 60 years of age. Population screening could prevent such deaths. Aortic diameter (which can be measured accurately on ultrasound) is a strong predictor of the risk of rupture, which is about 17% per year with aortic diameter > or = 6 cm, but below 0.5% per year with aortic diameter < 5 cm, with uncertainty regarding risk in the range 5.0-5.9 cm. Adopting an aortic diameter cut-off of 6.0 cm, the detection rate is estimated to be 86% (that is, 86% of all men who would rupture an aortic aneurysm could be identified and offered surgery) and the false positive rate only 0.6% (that is, 0.6% of men who would not rupture an aortic aneurysm would be so identified). In men with aortic diameter > or = 6 cm, the risk of rupture of 17% per year greatly outweighs the peri-operative mortality of about 5%. A national screening programme for men over 60 years of age could prevent 2000 deaths per year and should commence. Uncertainty remains regarding the frequency with which men with smaller aneurysms should be re-examined and the value of intervention among those with an aortic diameter of 5.0-5.9 cm, but the screening programme itself would generate data to help resolve these issues.

Copper salts for growth stimulation and alleviation of aortic rupture losses in turkeys.

Approximately 4000 Large White, day-old turkey poults were used in a series of eight experiments to study the effects of dietary copper supplementation. The hens were grown to 15 or 16 weeks and toms to 24 weeks of age. Either copper as the oxide or sulfate (hydrate) at 120 ppm stimulated growth up to 10% with a concurrent reduction in feed requirement. Levels of 60 ppm were not adequate, whereas 240 ppm were not toxic. There was a greater response to copper in the presence of 4-nitrophenylarsonic acid (4-nitro) or with low protein diets. In two of the eight studies copper enhanced aortic elastin content. Incidence of aortic rupture was greater in the presence of 4-nitro and was reduced by one-half through copper supplementation. Liver copper was not altered by 60 or 120 ppm Cu; 240 ppm caused a significant increase.