1. Atherosclerosis and aneurysm of the abdominal aorta are associated with thinning of the medial connective tissue. We have investigated the presence of the connective-tissue-degrading metalloproteinases in homogenates prepared from atherosclerotic, aneurysmal and control aortic media. 2. Gelatinase activity was much increased in homogenates from atherosclerotic and aneurysmal aorta [10.9 +/- 1.8 and 13.3 +/- 3.3 micrograms of gelatin hydrolysed h-1 (mg of protein)-1 respectively]. This gelatinase activity was highest at the luminal aspect of the aortic media, where the activity increased three- to five-fold after the destruction of alpha 2-macroglobulin. Zymograms demonstrated the principal gelatinase in atherosclerotic aorta to have a molecular mass of about 92 kDa, whereas in aneurysmal aorta there was a spectrum of gelatinase activity from 92 to 55 kDa. 3. Collagenase and stromelysin (proteoglycanase) could be detected by immunoblotting in homogenates of aneurysmal aorta, but rarely in atherosclerotic aorta and never in control aorta. Collagenase and stromelysin activities were low, but increased two- to three-fold after the destruction of tissue inhibitor of metalloproteinases. Collagenase and stromelysin activities were highest at the adventitial aspect of aneurysmal media. 4. The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning. Secretion of collagenase, gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aorta.
1. There is a familial tendency to abdominal aortic aneurysms. We have followed up a previous report of a weak association between the haptoglobin 2-1 phenotype and aortic aneurysm and investigated polymorphisms of the haptoglobin gene and neighbouring cholesterol ester transfer protein gene on the long arm of chromosome 16 in patients with atherosclerotic abdominal aortic aneurysm, patients with stenosing aortic atherosclerosis and healthy control subjects. The protein polymorphism of haptoglobin results from variant alpha-chains, alpha 1 and alpha 2, the phenotype nomenclature describing the two alpha-chains. We have also investigated whether the different haptoglobin phenotypes influence the degradation of aortic connective tissue. 2. The frequency of the haptoglobin alpha 1 allele was increased in patients with aneurysms compared with healthy control subjects (0.51 versus 0.35, P less than 0.05). Patients homozygous for the alpha 2 allele had the highest mean age at aneurysm resection. The frequency of a rare polymorphism at the cholesterol ester transfer protein locus was also increased in aneurysm patients (0.15 versus 0.05 in control subjects, P less than 0.01). These two genetic markers appear to act independently. Haptoglobins containing an alpha 1-chain accelerated two- to four-fold the degradation by elastases of aortic elastin in vitro. 3. Genetic variation in the haptoglobin and cholesterol ester transfer protein genes appears to influence dilatation of the abdominal aorta. Variation at the haptoglobin locus could have a direct effect on the degradation of elastin in atherosclerotic aorta, whereas variation at the cholesterol ester transfer protein locus could affect lipid metabolism and promote atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Phthalic acid esters concentration-dependently inhibited the formation of both cyclo-oxygenase and lipoxygenase arachidonate products by rat peritoneal leucocytes. Phthalates are extracted by human transfusion blood stored in pvc bags, and might similarly affect the blood cells when administered to patients.
Inhibition of prostaglandin formation from [14C]arachidonic acid by rat peritoneal leucocytes occurred with nonsteroidal anti-inflammatory drugs, their order of potency being indomethacin greater than piroxicam greater than naproxen greater than ibuprofen greater than isoxicam. At the lowest concentration tested (1 microgram ml-1), indomethacin markedly increased the accumulation of lipoxygenase products in the cell incubates. Naproxen, ibuprofen or piroxicam 1 or 10 micrograms ml-1 resulted in smaller increases of lipoxygenase products, and there was only a small rise with these concentrations of isoxicam.
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