Absence of Host Plasminogen Activator Inhibitor 1 Prevents Cancer Invasion and Vascularization

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis

Polymorphism of SERPINE2 gene is associated with pulmonary emphysema in consecutive autopsy cases

<p>Abstract</p> <p>Background</p> <p>The <it>SERPINA1</it>, <it>SERPINA3</it>, and <it>SERPINE2 </it>genes, which encode antiproteases, have been proposed to be susceptible genes for of chronic obstructive pulmonary disease (COPD) and related phenotypes. Whether they are associated with emphysema is not known.</p> <p>Methods</p> <p>Twelve previously reported single nucleotide polymorphisms (SNPs) in <it>SERPINA1 </it>(rs8004738, rs17751769, rs709932, rs11832, rs1303, rs28929474, and rs17580), <it>SERPINA3 </it>(rs4934, rs17473, and rs1800463), and <it>SERPINE2 </it>(rs840088 and rs975278) were genotyped in samples obtained from 1,335 consecutive autopsies of elderly Japanese people. The association between these SNPs and the severity of emphysema, as assessed using macroscopic scores, was determined.</p> <p>Results</p> <p>Emphysema of more than moderate degree was detected in 189 subjects (14.1%) and showed a significant gender difference (males, 20.5% and females, 7.0%; p < 0.0001). Among the 12 examined SNPs, only rs975278 in the <it>SERPINE2 </it>gene was positively associated with emphysema. Unlike the major alleles, homozygous minor alleles of rs975278 were associated with emphysema (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.02-2.30; p = 0.037) and the association was very prominent in smokers (OR = 2.02; 95% CI = 1.29-3.15; p = 0.002).</p> <p>Conclusions</p> <p><it>SERPINE2 </it>may be a risk factor for the development of emphysema and its association with emphysema may be stronger in smokers.</p

Collagen production in cardiac fibroblasts during inhibition of angiotensin-converting enzyme and aminopeptidases

Objective To determine whether lisinopril, an angiotensin converting enzyme (ACE) inhibitor, and bestatin, an aminopeptidase inhibitor with broad specificity, could affect collagen production in control and transforming growth factor (TGF)-beta(1) -treated cardiac fibroblasts. Design and methods Cardiac fibroblasts from passage 2 from normal male adult rats were cultured to confluency, incubated with or without 600 pmol/l TGF-beta(1) for 2 days in serum-free Dulbecco's modified Eagle's medium and then incubated with the test products (lisinopril or bestatin) for 1 day in this medium with added ascorbic acid, beta-aminoproprionitrile and tritiated proline. Soluble collagen was measured in the conditioned medium and non-soluble collagen in the cell layer. ACE activity was measured fluorimetrically with hippuryl-histidyl-leucine as substrate, and DNA with the bisbenzimide dye, Hoechst 33,258. Aminopepticlase activity was estimated by spectrophotometric determination of the liberation of p-nitroaniline from alanine-p-nitroanilide. Results Lisinopril dose-dependently reduced ACE activity in control and TGF-beta(1)-treated cardiac fibroblasts. Bestatin inhibited the basal and TGF-beta(1)-stimulated aminopeptidase activity in a concentration -depe n dent manner. Lisinopril (110 mumol/1) decreased (P < 0.05) the production of soluble and non-soluble collagen in control cardiac fibroblasts. TGF-beta(1) (600 pmol/1) increased (P< 0.05) the production soluble and non-soluble collagen, and this effect was decreased (P < 0.05) by lisinopril. Bestatin (1100 mumol/l) reduced (P < 0.01) the production of soluble collagen in control and TGF-beta(1) -treated cardiac fibroblasts, but did not affect the production of non-soluble collagen in these cells. Conclusions Our data suggest that ACE and aminopepticlases are involved in the basal and TGF-beta(1)-stimulated production of collagen in adult rat cardiac fibroblasts in culture. (C) 2004 Lippincott Williams Wilkins

Effect of bisoprolol and atenolol on endurance exercise capacity in healthy men

Objectives To compare the effects of a highly beta(1)-selective adrenoceptor antagonist bisoprolol with those of atenolol and placebo on endurance exercise capacity in young, healthy male volunteers. Design Twelve subjects randomly received oral placebo, atenolol (100 mg/day) or bisoprolol (10 mg/day) for 3 weeks, following a double-blind cross-over design. Methods At the end of each period, the subjects performed an endurance exercise test on the bicycle ergometer at 70% of maximal aerobic power. Cardiac output was measured by means of an automated CO2-rebreathing method. Venous blood was sampled before, during and after exercise. Results Exercise duration was not significantly different between the two drugs tested. Total exercise duration was significantly reduced by bisoprolol (-19.4 +/- 6.7%, P < 0.01) (mean +/- SEM) and by atenolol (-29.8 +/- 6.6%, P < 0.001), compared with placebo. Atenolol and bisoprolol were equally effective in lowering resting plasma renin activity, heart rate and systolic blood pressure. Resting and exercise stroke volume were significantly increased by both drugs, so that cardiac output was not significantly affected. Both drugs induced significant decreases in plasma-free fatty acid concentrations during recovery and blunted the exercise-induced increase. There were no significant relationships between the reduction of exercise duration and the haemodynamic changes or the degree of impairment of the exercise-induced increase in free fatty acid release resulting from beta-blockade. Conclusions It is concluded that both drugs affect endurance exercise capacity in young, normotensive men, with a tendency to a smaller reduction during bisoprolol treatment. Haemodynamic variables are unlikely to be involved in the reduction of endurance exercise capacity. The role of the reduced availability of plasma free fatty acids remains unclear. J Hypertens 2000, 18:35-43 (C) Lippincott Williams & Wilkins