VASCULAR BIOLOGY: Signaling decreased blood pressure

Blood pressure is controlled in part by changes in the radius of blood vessels; when the smooth muscle cells in the wall of a blood vessel contract, the radius of the blood vessel decreases and blood pressure increases. A team of researchers at CSIC-University of Salamanca, Spain, has now identified in mice a new signaling pathway that contributes to relaxation of smooth muscle cells in blood vessel walls triggered by the molecule NO and thereby decreases blood pressure.

Mice lacking the protein Vav2 have elevated blood pressure. By analyzing these mice, the team, led by Xosé Bustelo, identified a Vav2 signaling pathway that normally contributes to NO-triggered relaxation of smooth muscle cells in blood vessel walls. The pathway involves Vav2 activation of the proteins Rac1 and Pak1. Absence of Pak1 activation in Vav2-deficient mice resulted in excessive activity of the protein phosphodiesterase type 5. Consistent with this, treating Vav2-deficient mice with phosphodiesterase type 5 inhibitors reduced their blood pressure to a normal level. As defective blood vessel reactivity to NO contributes to the symptoms of diseases such as atherosclerosis (hardening of the arteries) and diabetes, the authors suggest that stimulating the pathway they have identified might be of therapeutic benefit in patients with these diseases.

TITLE: The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells

Xosé R. Bustelo
CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.

View this article at: jci/articles/view/38356?key=VFkTwWePlatxwBXqdW3x

ONCOLOGY: How cancer cells protect themselves from low levels of oxygen

Not all regions of a tumor are equal in terms of their oxygen levels. One clinically important implication of this is that tumors with large areas with low levels of oxygen (areas known as hypoxic regions) are associated with poor prognosis and treatment response. A team of researchers, led by Bradly Wouters, at the University of Toronto, Canada, has determined that a cellular response pathway known as the unfolded protein response pathway helps protect human tumor cells from hypoxia and anticancer irradiation treatment. Further analysis indicated that the unfolded response pathway increased expression of two proteins involved in a cellular process known as autophagy, which is known to act to protect cells in times of stress. Importantly, inhibition of autophagy sensitized cultured human tumor cells to hypoxia and sensitized human tumors xenografted into mice to irradiation, leading the authors to suggest that targeting the molecules they identified as important might be of clinical benefit.

TITLE: The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5

Bradly G. Wouters
University of Toronto, Toronto, Ontario, Canada.

View this article at: jci/articles/view/40027?key=R0gn8cJB89Pz98D0OF8t

METABOLISM: Bone control of glucose levels

Bone cells known as osteoblasts were recently shown to have a role in controlling the biochemical reactions that generate energy via secretion of the molecule osteocalcin. A team of researchers, led by Stavroula Kousteni, at Columbia University, New York, has now determined that the protein FoxO1 regulates this function of osteoblasts in mice. Specifically, FoxO1 increases expression of osteocalcin and decreases expression of Esp, a gene that makes a protein responsible for decreasing the bioactivity of osteocalcin. This is a new role for FoxO1, which is also involved in regulating glucose levels via effects on cells in the pancreas and liver.

TITLE: FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice

Stavroula Kousteni
Columbia University, New York, New York, USA.

View this article at: jci/articles/view/39901?key=IsEkHw3z3h7LJTXqmYDH

NEPHROLOGY: Soluble immune molecules cause acute kidney inflammation in mice

Immune molecules known as cytokines are effectors of immune cell function. The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have been linked to autoimmune diseases (i.e, diseases in which the immune system turns on the body). A team of researchers, led by Li Li, at the University of Virginia, Charlottesville, has now determined that these cytokine pathways also contribute to inflammation in a mouse model of acute kidney injury. Specifically, they find that the IL-23/IL-17 pathway works upstream of the IL-12/IFN-gamma pathway, as IL-17A production by immune cells known as neutrophils was required for activation of the IL-12/IFN-gamma pathway. In addition, as the inflammation underlying kidney injury in this model was caused by blood flow returning to the kidney following a period in which the kidney was deprived of blood flow (an event known as reperfusion) and reperfusion injury has a role in brain and heart damage caused by stroke and heart attack, respectively, the authors suggest that the IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways might contribute to reperfusion injury in other organs.

TITLE: IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury

Li Li
University of Virginia, Charlottesville, Virginia, USA.

View this article at: jci/articles/view/38702?key=Nwa5Q206lzzoF7Ydyxl4

Source: Karen Honey
Journal of Clinical Investigation

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