Rosmarinic Acid Suppresses Abdominal Aortic Aneurysm Progression in Apolipoprotein E-deficient Mice.

An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice via infusion of angiotensin II for 4 wks. Rosmarinic acid, salvianolic acid C, salvianolic acid B, or doxycycline as a positive control was provided daily through intraperitoneal injection. Administration of rosmarinic acid was found to decrease the thickness of the aortic wall, as determined by histopathological assay. Rosmarinic acid also exhibited protection against elastin fragmentation in aortic media and down-regulated cell apoptosis and proliferation in the aortic adventitia. Infiltration of macrophages, T lymphocytes, and neutrophils in aortic aneurysms was found, especially at the aortic adventitia. Rosmarinic acid, salvianolic acid C, or salvianolic acid B inhibited the infiltration on macrophages specifically, but these compounds did not influence T lymphocytes and neutrophils. Expression of matrix metalloproteinase 9 and macrophage migration inhibitory factor significantly increased in aortic aneurysms. Rosmarinic acid and salvianolic acid C decreased the expression of matrix metalloproteinase-9 in media, and rosmarinic acid also tended to reduce migration inhibitory factor expression. Further then, partial least squares-discriminate analysis was used to classify metabolic changes among different treatments. Rosmarinic acid affected most of the metabolites in the biosynthesis of the citrate cycle, fatty acid pathway significantly. Our present study on mice demonstrated that rosmarinic acid inhibited multiple pathological processes, which were the key features important in abdominal aortic aneurysm formation. Further study on rosmarinic acid, the novel candidate for aneurysmal therapy, should be undertaken to determine its potential for clinical use.

Reversal of Vascular Calcification and Aneurysms in a Rat Model Using Dual Targeted Therapy with EDTA- and PGG-Loaded Nanoparticles.

Degeneration of elastic lamina and vascular calcification are common features of vascular pathology such as aortic aneurysms. We tested whether dual therapy with targeted nanoparticles (NPs) can remove mineral deposits (by delivery of a chelating agent, ethylene diamine tetraacetic acid (EDTA)) and restore elastic lamina (by delivery of a polyphenol, pentagalloyl glucose (PGG)) to reverse moderate aneurysm development. EDTA followed by PGG NP delivery led to reduction in macrophage recruitment, matrix metalloproteinase (MMP) activity, elastin degradation and calcification in the aorta as compared to delivery of control blank NPs. Such dual therapy restored vascular elastic lamina and improved vascular function as observed by improvement in circumferential strain. Therefore, dual targeted therapy may be an attractive option to remove mineral deposits and restore healthy arterial structures in moderately developed aneurysms.

Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice.

Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE(-/-)) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.

[Effect of nifedipine on organ protection: potential application in patients with aortic aneurysm].

Useful drug therapy for inhibiting the extension of an aortic aneurysm or promoting its involution has not yet been established. Hypertension is a known risk factor for extension of an aortic aneurysm. However, on a cellular level it is believed that activation of nuclear factor (NF)-kappaB and matrix metalloproteinase (MMP) is involved in the extension of an aortic aneurysm. Nifedipine has been evaluated in a rat model of aortic aneurysm and it was found to inhibit activation of MMP and extension of the aortic aneurysm. Nifedipine also inhibited activation of NF-kappaB and these effects were independent of the antihypertensive effect of the drug. With antihypertensive and vasculoprotective effects and inhibitory actions on activation of NF-kappaB and MMP, nifedipine has potential to be a useful option in the drug treatment of patients with aortic aneurysm.

The diagnosis and management of hypertensive crises.

Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.

[Comparison of long-term results of surgical and nonsurgical therapy in acute aortic dissection].

The early and long-term results of both surgical and nonsurgical therapy for 160 patients with acute aortic dissection in our institution were analyzed. Of the 83 patients with acute type A aortic dissection, 47 received surgery during acute stage, 10 received it in the chronic stage, and 26 received nonsurgical therapy. Of the 77 patients with acute type B aortic dissection, 27 received surgery during acute stage, 22 received it in the chronic stage, and 28 received nonsurgical therapy. Ten-year survival rates for patients receiving surgery during the acute stage were 62% for type A and 64% for type B dissection. This survival rate for type A patients was significantly higher than that for type A patients not receiving surgery, but the corresponding difference for type B patients was not significant. Present data indicate that immediate surgical intervention is indicated in patients with acute type A dissection, and elective operation in the subacute stage in patient with uncomplicated type B dissection following medical therapy in the acute stage.