Elastin stabilization for treatment of abdominal aortic aneurysms.

BACKGROUND: Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development. METHODS AND RESULTS: Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl2-mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells. CONCLUSIONS: Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.

The mechanical function and structure of aortic microfibrils in the lobster Homarus americanus.

Marfan syndrome, a connective tissue disorder affecting the cardiovascular system, is caused by mutations of fibrillin-based microfibrils. These mutations often affect the calcium-binding domains, resulting in structural changes to the proteins. It is hypothesized that these Ca+2 binding sites regulate the structure and mechanical properties of the microfibrils. The mechanical properties of fresh and extracted lobster aortic rings in calcium solutions (1, 13 and 30 mM Ca+2) were measured. Samples underwent amino acid compositional analysis. Antibodies were produced against the material comprising extracted aortic rings. The ultrastructure of strained and unstrained samples was examined using transmission electron microscopy. Calcium level altered the tangent modulus of fresh vessels. These rings were significantly stiffer when tested at 30 mM Ca+2 compared to rings tested at 1 mM Ca+2. Amino acid comparisons between extracted samples, porcine and human fibrillin showed compositional similarity. Immunohistochemical analysis showed that antibodies produced against the material in extracted samples localized to the known microfibrillar elements in the lobster aorta and cross-reacted with fibrillin microfibrils of mammalian ciliary zonules. Ultrastructurally, vessels incubated in low calcium solutions showed diffuse interbead regions while those incubated in physiological or high calcium solutions showed interbead regions with more defined lateral edges.

Stimulation of perivascular nitric oxide synthesis by oxygen.

We hypothesized that elevated partial pressures of O(2) would increase perivascular nitric oxide (*NO) synthesis. Rodents with O(2)- and.NO-specific microelectrodes implanted adjacent to the abdominal aorta were exposed to O(2) at partial pressures from 0.2 to 2.8 atmospheres absolute (ATA). Exposures to 2.0 and 2.8 ATA O(2) stimulated neuronal (type I) NO synthase (nNOS) and significantly increased steady-state.NO concentration, but the mechanism for enzyme activation differed at each partial pressure. At both pressures, elevations in.NO concentration were inhibited by the nNOS inhibitor 7-nitroindazole and the calcium channel blocker nimodipine. Enzyme activation at 2.0 ATA O(2) appeared to be due to an altered cellular redox state. Exposure to 2.8 ATA O(2), but not 2.0 ATA O(2), increased nNOS activity by enhancing nNOS association with calmodulin, and an inhibitory effect of geldanamycin indicated that the association was facilitated by heat shock protein 90. Infusion of superoxide dismutase inhibited.NO elevation at 2.8 but not 2.0 ATA O(2). Hyperoxia increased the concentration of.NO associated with hemoglobin. These findings highlight the complexity of oxidative stress responses and may help explain some of the dose responses associated with therapeutic applications of hyperbaric oxygen.

Accumulation of calcium and phosphorus in the mitral valve in comparison with the abdominal aorta and the scaphoid bone.

To clarify why calcification of the mitral valve occurred, the authors chose the abdominal aorta and the scaphoid bone among many arteries and bones, and they studied both relationships in element contents between the mitral valve and the abdominal aorta and between the mitral valve and the scaphoid bone. The subjects consisted of 11 men and 8 women, ranging in age from 52 to 96 yr. The accumulation of calcium and phosphorus occurred progressively with aging in the mitral valve, whereas it became the highest in the sixties in the abdominal aorta and did not increase thereafter. The accumulation of calcium and phosphorus occurred in the abdominal aorta earlier than the thoracic aorta, in which it became remarkable in the seventies. It should be noted that in regard to the accumulation of calcium and phosphorus, no significant correlations were found between the mitral valve and the abdominal aorta. It is suggested that calcification of the abdominal aorta is not essentially accompanied by calcification of the mitral valve. The scaphoid bone was chosen among many bones consisting mainly of spongy bone and the relationship was examined between the calcium content in the mitral valve and the bone mineral density of the scaphoid bone. It was found that there was a low relationship between them. Therefore, it is suggested that a part of the surplus calcium released from bones is deposited in the mitral valve.

[Qualitative change in the elastin from the calcified portion of human artery].

To examine the qualitative changes of elastin and the aorta related to calcification of human arteries, biochemical properties were measured, including calcium (Ca), phosphorus (P) and magnesium (Mg) contents in the aorta or in the elastin fraction in calcification, cholesterol content in atherosclerosis, desmosine content of cross-link, free thiol contents (free SH/total SH) and hydrophobic properties in the elastin fraction from the calcified portion, adjacent sites and another normal artery. The results from different sites of the calcified abdominal artery are as follows: The contents of Ca, P and Mg in aorta and the elastin fraction from the calcification site were higher than those at other sites. Moreover, Ca in the aorta and elastin fraction correlated positively with P and Mg. The content of cholesterol in the calcification site was the same as at other sites and did not correlate with Ca, P or Mg. The content of desmosine in the calcification site was significantly lower than that in different sites. In addition, its content was negatively associated with Ca and P in the elastin fraction and with the aortic Mg. The content of free thiol in the calcification site was similar to the other sites and correlated negatively with Ca and P in the aorta. The hydrophobicity in the calcification was similar to that at other sites, and was negatively associated with Ca and Mg in the elastin fraction.

[The effect of heparin in vasorenal hypertension on the rheological properties of the erythrocytes and on the electrolyte balance of the blood and of the wall of the abdominal aorta]. / Vliianie geparina pri vazorenal'noi gipertenzii na reologicheskie svoistva éritrotsitov, balans élektrolitov krovi i stenki briushnoi aorty.

In hypertension there was shown an increase of the erythrocyte suspension viscosity coefficient, a decrease of the transmural difference of the abdominal aorta potentials and the erythrocyte charge at a lowering of the level of the studied electrolytes in plasma, the abdominal aorta wall and an increase of sodium content in erythrocytes. Heparin corrected the changes in the coefficient of viscosity and charge of erythrocytes, the transmural difference of potentials, potassium and magnesium levels in erythrocytes, sodium level in the abdominal aorta wall induced by hypertension. On the whole there was observed no levelling by heparin of electrolyte imbalance in the erythrocyte-plasma-abdominal aorta wall system.