June 27, 2008

Aliquots — Research highlights from VUMC laboratories

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We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.

Calcification predicts amputation

The buildup of calcium in blood vessels contributes to peripheral artery disease (PAD), a condition of decreased circulation in arteries that, in limbs, can eventually require amputation. The ankle-brachial index (ABI) – a ratio of ankle to arm blood pressure, which indicates compromised circulation – has traditionally been used to diagnose PAD and assess a patient’s risk for future leg problems. But predicting which patients will require amputation remains difficult.

Raul Guzman, M.D., and colleagues now show that measuring tibial artery calcification (TAC) – the amount of calcium buildup in the tibial artery – by multislice computed tomography provides a better indicator of amputation risk than the ABI. Patients with TAC scores greater than 400 had significantly increased risk of amputation. Their findings, in the May 20 issue of the Journal of the American College of Cardiology, suggest that measuring TAC may be useful in guiding limb preservation therapies for those with PAD – such as more frequent foot examinations, custom shoes and intensive medical therapy.

— William Peters

Heartbeat helper

Electrical currents, generated by the movement of charged molecules (e.g., sodium, potassium and calcium) into and out of cells, power the heart. One type of current, called IKur, is considered a potential target for treating atrial arrhythmias. While a protein called KCNA5 is primarily responsible for IKur, researchers suspect that other proteins must associate with KCNA5 for proper channel function.

Katherine Murray, M.D., and colleagues have identified a key protein partner of KCNA5 – called “four and a half LIM” (or FHL1) – in the human atrium. In the June issue of Cardiovascular Research, they show that the expression of FHL1 in conjunction with KCNA5 markedly increases the amount of current going through a given patch of cell membrane, alters channel opening, and enhances mechanisms that turn the current off. The results suggest that FHL1 is a key component of the IKur complex and is critical for normal cardiac function. Based on this important role, FHL1 dysfunction in humans may underlie some arrhythmias and cardiomyopathies.

— Melissa Marino

Security team for the genome

Genome “surveillance systems” detect and respond to DNA damage to maintain the genome’s stability and prevent cancer. One such system includes the protein kinase ATR and its regulatory partner ATRIP.

To gain insight into how ATR-ATRIP complexes are activated by DNA damage, Daniel Mordes, David Cortez, Ph.D., and colleagues examined the interaction between this complex and an activating protein – TopBP1. They report in the June 1 Genes & Development that TopBP1 activates ATR by interacting with protein surfaces on both ATR and ATRIP. These interactions are required for cells to survive and recover DNA synthesis following replication stress (slowed or stalled DNA replication). Importantly, the investigators also determined that the mechanism of ATR regulation is shared by related genome-maintaining kinases.

These results provide a starting point for designing agents to disrupt genome surveillance systems and sensitize cancer cells to many chemo-therapy drugs.

— Leigh MacMillan

Brain says, ‘Make more fat’

Elevated triglyceride (TG) – the main form of dietary fat that circulates in the blood – contributes to the increased risk of cardiovascular disease in obese and diabetic patients. To identify novel mechanisms that lead to elevated blood TG, Kevin Niswender, M.D., Ph.D., and colleagues including endocrinology fellow John Stafford, M.D., Ph.D., looked to the brain. Growing evidence suggests that brain signaling systems function as metabolic sensors – they “read” signals from the body and coordinate changes in energy stores and energy demand.

The investigators found that injecting neuropeptide Y (NPY), known to activate metabolic sensor-type neurons, directly into rats’ brains increased TG secretion from the liver. An NPY receptor agonist also increased TG secretion, and an NPY receptor antagonist reduced TG secretion by 50 percent. The findings, reported in the June Diabetes, show that NPY-signaling neurons exert control over TG secretion into the bloodstream, adding to the evidence that brain systems have a role in liver fat metabolism.

— Leigh MacMillan

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012