Influence of cardiovascular risk factors on levels of matrix metalloproteinases 2 and 9 in human abdominal aortic aneurysms.

OBJECTIVE: To evaluate the influence of cardiovascular risk factors on levels of matrix metalloproteinases (MMP) 2 and 9 in human abdominal aortic aneurysms (AAA). METHODS: Aortic samples were collected from patients who underwent AAA repair (n = 89). Patients were stratified according to the maximum transverse aorta diameter: small diameter (<55 mm), moderate diameter (55-69.9 mm) and large diameter (≥70 mm). Aortic walls were studied using real-time PCR and immunohistochemistry. MMP-2, MMP-9, α-actin, CD45, and CD68 transcript levels were determined relative to ß-actin. Quantitative data were expressed as median (IQ-range). RESULTS: No differences were found in MMP-2 expression between the patient groups, which was mainly associated with vascular smooth muscle cells (VSMC); however, MMP-9 displayed the maximum level in the moderate-diameter group, associated with infiltrating macrophages. Current smoking (CS) and renal insufficiency (RI) significantly increased local levels of MMP-2 (CS 349.5 [219.5-414.1] vs. no-CS 184.4 [100.0-320.5]; p < .008; RI 286.8 [189.6-410.8] vs. no-RI 177.3 [99.3-326.9]; p = .047). Nevertheless, after stepwise linear regression analysis only CS remained as an independent variable predicting local levels of MMP-2 (p = .002). No risk factors influenced local levels of MMP-9. CONCLUSIONS: The results show that local levels of MMP-2, an important factor for AAA development, were increased in current smoking AAA patients. MMP-2 was mainly associated with VSMC. It is suggested that MMP-2 could contribute significantly to the increased AAA growth rate observed in current smoking patients. These findings support inclusion of smokers in screening for aneurysmal disease, and emphasize the need for more aggressive monitoring of aneurysmal disease outside the surgical range in patients who smoke at the time of diagnosis and in those who continue to smoke during follow-up.

IL-1beta induces VEGF, independently of PGE2 induction, mainly through the PI3-K/mTOR pathway in renal mesangial cells.

Vascular endothelial growth factor (VEGF) could play a relevant role in angiogenesis associated with chronic allograft nephropathy. Interleukin-1beta (IL-1beta) has a key role in inflammatory response. It induces prostaglandin (PG) E2, which is involved in VEGF release by some normal and tumor cells. In the present work, we studied the effect of IL-1beta on VEGF release by rat mesangial cells, the transduction signal, and whether or not PGE2 is involved in this effect. IL-1beta induced a time-dependent formation of VEGF (analyzed by enzyme-linked immunosorbent assay) and PGE2 (analyzed by enzyme immunoassay). The latter correlated with microsomal-PGE-synthase (mPGES)-1 expression rather than with cyclooxygenase (COX)-2 in terms of protein, determined by Western blotting. No effect of IL-1beta on COX-1, cytosolic PGES, or mPGES-2 expression was observed. Indomethacin exerted a nonsignificant effect on IL-1beta-induced VEGF, and exogenously added PGE2 exhibited a nonsignificant stimulatory effect on VEGF formation. SB 203580, a p38 mitogen-activated protein kinase inhibitor, weakly inhibited the induction of VEGF by IL-1beta in a concentration-dependent manner, whereas LY 294002, a phosphoinoside 3-kinase (PI3-K) inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, strongly inhibited both IL-1beta- and tumor necrosis factor-alpha-induced VEGF formation in a concentration-dependent manner. Rapamycin also decreased glomerular VEGF levels in the anti-Thy1.1 model of experimental glomerulonephritis. In conclusion, the PI3-K-mTOR pathway seems to be essential in cytokine-induced release of VEGF in mesangial cells.