Intramural papers of the month
- Chloride channel regulation may lead to improvements in vascular disease
- Mechanisms of anticancer drug resistance
- New insights into lung dendritic cell migration in adaptive immune responses
- Tobacco smoke exposure in utero increases adult cardiovascular disease risk
Chloride channel regulation may lead to improvements in vascular disease
A recent NIEHS-funded study determined that the migration of vascular smooth muscle cells (VSMCs) is regulated by chloride ion flux through chloride channel ClC-3. The team is the first to show that the chloride current dramatically decreases in VSMCs lacking the ClC-3 protein and that calmodulin-dependent protein kinase II (CaMKII), a mediator of calcium signaling, acts through ClC-3 to stimulate the chloride current in VSMCs. Since VSMC migration causes health conditions such as high blood pressure (hypertension), artery hardening (atherosclerosis), and artery re-narrowing following corrective surgery (restenosis), understanding these cellular signals may aid the development of medicines that will inhibit vascular remodeling.
Through electrophysiological recordings of aortic VSMCs from wild-type mice and mice without the ClC-3 gene, the researchers found that the chloride current of the ClC-3-knockout VSMCs was about half that of the wild-type cells. These findings indicate that there are two components to the chloride current — a ClC-3-dependent and ClC-3-independent. Additionally, the chloride channel blocker niflumic acid inhibited migration of wild-type VSMCs but has no further effect on the knockout cells, suggesting that the ClC-3-dependent component was more important in VSMC migration.
The scientists also demonstrated that inositol-3,4,5,6-tetrakisphosphate (IP4) reduced ClC-3-mediated VSMC migration without altering CaMKII activity; IP4 may be a lead compound for developing therapeutic drugs to specifically target ClC-3. (SY)
Citation: Ganapathi SB, Wei SG, Zaremba A, Lamb FS, Shears SB. 2012. Functional regulation of CIC-3 in the migration of vascular smooth muscle cells. Hypertension 61(1):174-179.
Mechanisms of anticancer drug resistance
A new study published by NIEHS scientists describes the molecular mechanisms by which topoisomerase II (topo II)-DNA adducts are repaired by the mammalian tyrosyl-DNA phosphodiesterase 2 (Tdp2) enzyme. Since some of the most successful cancer chemotherapeutics work by inducing topo II-DNA adducts that promote cancer cell death, this study determines how Tdp2, in turn, contributes to anticancer drug resistance through its topo II-DNA adduct repair functions.
Visiting fellow Matthew Schellenberg. Ph.D., and biologist Denise Appel employed X-ray crystallography and biochemical analyses to determine how Tdp2 dictates a repair pathway that is critical for cells dealing with bulky topo II-DNA adducts. Topoisomerases play critical roles in enabling cellular DNA replication and transcription. However, stressors including environmental toxicants can interrupt the topo2 DNA processing reaction, thereby generating topo II-DNA adducts that can block the replication and transcription machinery. Tdp2 dictates a repair pathway by recognizing and removing these topo II-DNA adducts. The researchers trapped Tdp2 in a number of conformations bound to DNA that enabled them to define the protein-DNA conjugate processing mechanism at the atomic level.
This study has future implications in devising strategies to prevent anticancer drug resistance by targeting Tdp2 and developing Tdp2 inhibitors. (SP)
Citation: Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS. 2012. Mechanism of repair of 5’-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. Nat Struct Mol Biol 19(12):1363-1371. Story (https://www.niehs.nih.gov/news/newsletter/2012/11/science-anticancer/index.htm)
New insights into lung dendritic cell migration in adaptive immune responses
A recent report by NIEHS investigators found that the chemokine receptor CCR7, which is important in the migration of dendritic cells (DCs) to draining lymph nodes (LNs), is expressed in CD103+ DCs and a small population of CD11b-hi DCs. Both of these cell types are subsets of classical DCs (cDCs) and display migratory potential. In contrast, the team found that monocyte-derived DCs (moDCs) do not express CCR7 and are non-migratory. The data furthers the understanding of the migratory potential of DCs and provides important implications for therapeutic intervention for pulmonary diseases.
Pulmonary DCs are immune cells, which primarily function to process inhaled antigens and migrate to LNs for presentation to naïve T cells, thereby initiating an adaptive immune response. DC migration is a crucial event because naïve T cells are not abundant in peripheral tissues, but rather circulate between the blood and lymphoid tissues such as lymph nodes. Until this study, it was unknown whether all DC subsets possessed migratory properties.
Using mice deficient in the fms-like tyrosine kinase 3 ligand (FLT3L), a glycoprotein known to regulate the development of some DCs, the investigators found that all of the migratory DCs in the lung are in fact FLT3L-dependent cDCs. Thus, they concluded that the migratory properties of pulmonary DCs are dependent on their developmental lineage. (DT)
Citation: Nakano H, Burgents JE, Nakano K, Whitehead GS, Cheong C, Bortner CD, Cook DN. 2012. Migratory properties of pulmonary dendritic cells are determined by their developmental lineage. Mucosal Immunol; doi:10.1038/mi.2012.106 [Online 21 November 2012].
Tobacco smoke exposure in utero increases adult cardiovascular disease risk
In a new study, NIEHS Epidemiology Branch scientists reported that exposure to tobacco smoke in utero led to increased levels of triglycerides and lower levels of high-density lipoprotein cholesterol (HDL), also known as good cholesterol, in adulthood, 18-44 years after exposure.
The study included 479 pregnant women from the Norwegian Mother and Child Cohort Study (MoBa). The researchers also found that after adjusting for age, physical activity, education, personal smoking, and body mass index (BMI), there was no significant effect on low-density lipoprotein cholesterol (LDL), total cholesterol, apolipoprotein B, and C-reactive protein.
At study enrollment, women were asked about their mother’s smoking while pregnant with them; this information was used to assign in utero exposure. Standard clinical tests on nonfasting blood specimens followed by rigorous statistical analysis led them to conclude that women exposed to tobacco smoke in utero were twice as likely to have elevated triglycerides or low HDL.
This study has significant implications in understanding how exposure to tobacco smoke in utero relates to the risks of developing metabolic alterations and cardiovascular disease years after exposure. Studies in the past have only looked at effects in early childhood. (BR)
Citation: Cupul-Uicab LA, Skjaerven R, Haug K, Travlos GS, Wilson RE, Eggesbo M, Hoppin JA, Whitworth KW, Longnecker MP. 2012. Exposure to tobacco smoke in utero and subsequent plasma lipids, apoB, and CRP among adult women in the MoBA cohort. Environ Health Perspect 120(11):1532-1537.
(Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Bhargavi Rao, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Molecular Carcinogenesis. Darshini Trivedi, Ph.D., is an IRTA fellow in the NIEHS Laboratory of Toxicology and Pharmacology. Sheila Yong, Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction.)