Cardiovascular disease: Heartfelt complement

Activation of the complement cascade after myocardial infarction contributes to damage of heart tissue. Madhu Singh et al. now show that cardiomyocytes themselves contribute to this damage by producing complement factor B (CFB), resulting in injury to the cardiomyocyte cell membrane (J. Clin. Invest. doi:10.1172/JCI35814). CFB likely injures cardiomyocytes through formation of the membrane attack complex, a pore that permeabilizes and damages cells.

Examining infarcted mouse hearts, the researchers identified CFB as a target of calcium/calmodulin-dependent protein kinase II (CaMKII), which has a central role in promoting heart injury after myocardial infarction. They then found that CFB expression by cultured cardiomyocytes can damage them, and that CFB-deficient mice were partially protected from myocardial heart damage induced by infarction. Cardiomyocytes also produced CFB in response to inflammatory stimuli, a response that involved CaMKII activation of the nuclear factor-κB pathway.

Induction of CFB expression adds another mechanism to the many ways in which CaMKII signaling damages the heart after myocardial infarction. These results also point to the possibility that CaMKII may promote heart damage under inflammatory conditions such as sepsis. MB

Cancer: Vessel rehabilitation

Normalizing the leaky and misshapen blood vessels of a tumor impedes metastasis, report Massimiliano Mazzone et al. (Cell 136, 839–851). These findings support the idea that shoring up the tumor vasculature may prove to be a better therapeutic strategy than cutting off the blood supply.

Well-ordered cells in the tumor vessels of PHD2 heterozygous mice. Credit: Cell Press

Poor oxygenation as a result of tortured tumor vasculature may contribute to metastasis. To explore this phenomenon, Mazzone et al. studied the growth of tumors in mice heterozygous for the prolyl hydroxylase PHD2, required for the degradation of hypoxia inducible factor (HIF), which promotes tumor angiogenesis under low oxygen conditions. Because PHD2 heterozygosity increases the level of HIF, the authors anticipated that tumors in these mice would have increased tumor vasculature and metastasize more readily. But they found no difference in tumor vessel number or density in heterozygous mice compared with wild-type mice. Instead, tumors in heterozygous mice showed improved blood vessel function, reduced leakiness, increased tumor oxygenation and decreased metastasis.

The researchers attributed these changes to smoother, less porous endothelial cell lining of blood vessels and altered endothelial cell shape. The authors suggest that lowering PHD2 amounts in endothelial cells could be a therapeutic goal to normalize tumor vasculature, increase tumor oxygenation and thereby remove one of the triggers of metastasis. Whether such a strategy will work in the patient's or in the tumor's favor remains an open question. AF

Metabolic disorders: One more soda?

Diets high in fructose, such as those of heavy soda drinkers, have been linked to metabolic disturbances such as elevated fatty acids in blood, nonalcoholic fatty liver disease and insulin resistance—a feature of type 2 diabetes. A recent paper in Cell Metabolism (Cell Metab. 9, 252–264) reports on a molecular mechanism responsible for this link.

The mechanism involves peroxisome proliferator–activated receptor-γ coactivator-1b (PGC-1b). This molecule activates SREBP-1, a transcription factor that prompts the synthesis of lipids from sugars in the liver. By knocking down expression of PGC-1b in the liver and fat, Yoshio Nagai et al. explored whether PGC-1b participated in fructose-induced insulin resistance. They found that reducing the levels of PGC-1b inhibited SREBP-1 expression, reversed fructose-induced insulin resistance and promoted glucose uptake by adipose tissue.

These data indicate that targeting PGC-1b has the potential to turn back the metabolic disturbances associated with high-fructose diets. JCL

Written by Michael Basson, Alison Farrell, Juan Carlos López and Charlotte Schubert

New from NPG

Tumours with PI3K activation are resistant to dietary restriction Kalaany, N.Y. & Sabatini, D.M. Nature published online, doi:10.1038/nature07782 (11 March). Mutations in PI3K help explain why only some tumors respond to reductions in food intake.

Haematopoietic stem cells depend on Gαs-mediated signaling to engraft bone marrow Adams, G.B. et al. Nature published online, doi:10.1038/nature07859 (25 March). Activators of a G protein subunit enhance engraftment and homing of hematopoietic stem and progenitor cells to the bone marrow.

A mechanosensitive transcriptional mechanism that controls angiogenesis. Mammoto A, et al. Nature 457, 1103–1108. Transcription factors that control angiogenesis are shown to respond to both chemical and mechanical cues, providing a handle on how blood vessels navigate the extracellular matrix.

A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms Olcaydu, D. et al. Nat. Genet. published online, doi:10.1038/ng.341 (15 March).

A common version of the JAK2 gene may increase susceptibility to a cancer-associated mutation acquired in the soma.

Nicotine binding to brain receptors requires a strong cation-π interaction. Xiu, X., Puskar, N.L., Shanata, J.A., Lester, H.A. & Dougherty, D.A. Nature published online, doi:10.1038/nature07768 (1 March).

Credit: Wolfe Gleitsman

Subtle structural differences explain why acetylcholine receptors in the brain respond to nicotine, whereas receptors in the muscle largely ignore the drug. The study provides insight into drug design for a range of disorders.