Role of Gab1 in Postnatal Angiogenesis (p 664)
Blood vessels get growing with Gab1, report Shioyama et al.
Grb2-associated binder 1 (Gab1) is an intracellular protein that amplifies signals triggered by extracellular factors, such as cytokines, antigens, and growth factors. Shioyama et al wondered whether blood vessel development, a process regulated by growth factors, might therefore require Gab1. Mice that lack this protein die as embryos, having failed to properly develop organs, such as the heart, skin, and muscle. The team thus removed Gab1 specifically from mouse vascular endothelial cells to see if blood vessel growth was impaired. It was. Newborn wild-type mice that had their femoral arteries ligated to induce hind limb ischemia underwent a period of angiogenesis after ligature removal, but the hind limbs of mice lacking endothelial cell Gab1 did not similarly recover. Although a number of growth factors promote angiogenesis, the team showed that HGF was the main activator of Gab1. HGF treatment induced Gab1 phosphorylation and promoted the association of Gab1 with signaling factors and downstream activation of Gab1 target genes. Gab1 could, thus, become a target for pro- or antiangiogenic therapies of the future.
PM Induces Inflammation via TLR4 Pathways (p 716)
Kampfrath et al show how chronic air pollution puts us at risk for cardiovascular disease.
Inhalation of airborne particulates is known to be bad for our health. As well as causing lung problems, air pollution is also associated with an increased risk of cardiovascular diseases, such as atherosclerosis. It has been proposed that inflammatory responses in the lungs lead to the development of secondary systemic inflammation, which causes the cardiovascular problems, but the mechanisms behind this inflammation are unknown. Kampfrath et al have shown that fluid from the lungs of mice exposed chronically to airborne particles had increased levels of oxidized phospholipids. These molecules induced both inflammatory gene expression and cytokine production in monocytes. Monocytes lacking the cell surface receptor called TLR4, however, were resistant to the oxidized phospholipid effect. TLR4 deficiency also attenuated the rise in peripheral monocyte numbers seen in wild-type animals in response to chronic particle exposure. Reactive oxygen species production by these monocytes was also reduced. TLR4 is a member of a family of receptors that recognize a broad array of environmental and pathogenic antigens and that act as a first line of host defense. Here, Kampfrath et al suggest how this front line molecule could potentially amplify localized lung inflammation to become systemic after chronic air pollution exposure.
Human Resistin Stimulates Hepatocyte ApoB (p 727)
Block resistin to lower bad cholesterol, say Costandi et al.
Overweight individuals are at risk of atherosclerosis, in part, because of dyslipidemia, which is an overabundance and imbalance of lipids in their bloodstream. This imbalance is primarily due to an increase in the amount of low-density lipoproteins (bad cholesterol) relative to high-density lipoproteins (good cholesterol). Elevated levels of low-density lipoprotein (LDL) are correlated with high plasma levels of resistin, a factor secreted from fatty tissue. Experiments in mice have shown that high plasma resistin can directly boost LDL levels. Costandi et al were concerned, however, that these experiments had used unphysiologic levels of resistin. What's more, they say, it cannot be assumed that mouse and human resistin behaves the same way; indeed, the human and mouse resistin genes differ considerably. The team, thus, studied the effect of physiologic levels of human resistin on human hepatocytes. Their experiments supported the results seen in mice and also pointed to the mechanisms involved in increased LDL production. Resistin increased the activity of a protein called MTP, which loads LDL onto apoB (the plasma LDL transporter), and it reduced insulin signaling, known to enhance apoB stability. Although further details of these mechanisms are yet to be discovered, the results indicate that reduction in resistin activity might lead to lower LDL levels and, thus, a lower risk of atherosclerosis.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.