Publications

OBJECTIVE

Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation.

METHODS AND RESULTS

Low-density lipoprotein receptor-deficient (LDLr-/-) mice were lethally irradiated and reconstituted with bone marrow-derived cells from TERT-deficient (TERT-/-) mice or littermate wild-type mice. Mice were placed on a diet enriched in cholesterol, and AAA formation was quantified after 4 weeks of Ang II infusion. Repopulation of LDLr-/- mice with TERT-/- bone marrow-derived cells attenuated Ang II-induced AAA formation. TERT-deficient recipient mice revealed modest telomere attrition in circulating leukocytes at the study end point without any overt effect of the donor genotype on white blood cell counts. In mice repopulated with TERT-/- bone marrow, aortic matrix metalloproteinase-2 (MMP-2) activity was reduced, and TERT-/- macrophages exhibited decreased expression and activity of MMP-2 in response to stimulation with Ang II. Finally, we demonstrated in transient transfection studies that TERT overexpression activates the MMP-2 promoter in macrophages.

CONCLUSIONS

TERT deficiency in bone marrow-derived macrophages attenuates Ang II-induced AAA formation in LDLr-/- mice and decreases MMP-2 expression. These results point to a previously unrecognized role of TERT in the pathogenesis of AAA.

OBJECTIVE

Disease activity and medication use can complicate pregnancies in patients with systemic lupus erythematosus (SLE). We therefore examined contraceptive counseling and use among women in the University of California, San Francisco Lupus Outcomes Study.

METHODS

In 2008, we queried participants regarding their pregnancy intentions, contraceptive use, and receipt of contraceptive counseling. Premenopausal women age <45 years who were sexually active with men were considered at risk of pregnancy. We compared self-reported rates of contraceptive counseling and use stratified by treatment with teratogenic medications and by history of thrombosis or antiphospholipid antibodies (aPL), using chi-square tests. We used logistic regression models to examine predictors of contraceptive counseling and use.

RESULTS

Among 206 women, 86 were at risk for unplanned pregnancy. Most (59%) had not received contraceptive counseling in the last year, 22% reported inconsistent contraceptive use, and 53% depended solely on barrier methods. Intrauterine device contraceptives (IUDs) were used by 13%. Women using potentially teratogenic medications were no more likely to have received contraceptive counseling, to have used contraception consistently, or to have used more effective contraceptives. A history of thrombosis or aPL did not account for low rates of hormonal methods. Four women with a history of thrombosis or aPL were using estrogen-containing contraceptives.

CONCLUSION

Most women at risk for unplanned pregnancy reported no contraceptive counseling in the past year, despite common use of potentially teratogenic medications. Many relied upon contraceptive methods with high failure rates; few used IUDs. Some were inappropriately using estrogen-containing contraceptives. These findings suggest the need to improve the provision of contraceptive services to women with SLE.

We have investigated whether rat Ly49 receptors can monitor Listeria-infected intestinal epithelial cells through altered expression of MHC class I molecules. The rat colon carcinoma epithelial cell line CC531 infected with Listeria expressed higher levels of both classical and nonclassical MHC-I molecules. Reporter cells expressing the activating Ly49s5 receptor displayed increased stimulatory responses when incubated with Listeria-infected CC531 cells in vitro, which could be blocked with mAb 8G10 specific for nonclassical MHC-I molecules of the RT1(u) haplotype, but not with mAb OX18 reacting with classical MHC-I molecules in this haplotype. Similar responses were observed against IFN-γ-treated cells that also upregulated their expression of MHC-I molecules. Thus, the Ly49s5 receptor can respond to increased levels of nonclassical MHC-I molecules induced on target cells by either bacterial infection or cytokine stimulation. We furthermore found that splenic NK and NKT cells produced IFN-γ in response to Listeria-infected CC531 cells, and that this was not limited to Ly49-expressing cells, since similar levels of IFN-γ production were observed in Ly49(+) and Ly49(-) NK cell subsets. Therefore, NK cells may recognize Listeria-infected cells through both MHC-I-dependent and -independent innate immune receptor systems.