Research roundup

From the Winter 2019 edition of Vanderbilt Medicine Magazine

Study suggests way to prevent rare lung disease

Research by Vanderbilt scientists suggests that it may be possible to prevent or even reverse pulmonary arterial hypertension (PAH), a rare, progressive disease characterized by narrowing of and high blood pressure in the small arteries of the lungs.

A key player in PAH is the proangiogenic cell (PAC), a cell produced by the bone marrow that normally promotes the growth of new blood vessels.

In Circulation Research the researchers reported finding PACs in the stiffened small blood vessels in the lungs of patients with PAH. In cell culture studies, they showed that PACs aggravate damage to the blood vessel lining, leading to scarring and narrowing.

They showed they could both prevent and reverse experimentally induced pulmonary hypertension in a mouse model by killing off the PACs, and also by giving a drug that blocked signaling through a serotonin receptor called 5-HT2B.

“We were quite surprised to find out that the driver of pulmonary hypertension appears to be a very small population of cells from the bone marrow,” said the paper’s corresponding author, W. David Merryman, PhD, professor of Biomedical Engineering, Pharmacology, Medicine and Pediatrics.

 

Obesity negates beneficial drug effects

Blocking CETP — a protein that shuttles cholesterol and triglycerides between lipoproteins such as HDL and LDL — has been shown to improve levels of the “good” cholesterol HDL. Outcomes from clinical trials of CETP inhibitors, however, have not demonstrated robust decreases in the risk of cardiovascular disease.

Because many participants in the CETP inhibitor trials were obese, Lin Zhu, MD, PhD, John Stafford, MD, PhD, and colleagues wondered if obesity affected the response to CETP inhibition. They studied the effects of anacetrapib, a CETP inhibitor, in transgenic mice expressing CETP. They report that although CETP inhibition improved HDL levels in diet-induced obese mice, it increased liver inflammation and worsened insulin resistance compared to mice on a low-fat diet.

Their findings, reported in the journal Diabetes, suggest that the effects of CETP inhibition on HDL functionality are greatly influenced by high-fat diet-induced obesity and hyperlipidemia.

 

Vitamin C protects brain from seizures

Alzheimer’s patients are five to 10 times more likely to suffer unprovoked seizures compared to healthy individuals. Alzheimer’s patients often also have reduced levels of ascorbate, or vitamin C, an important antioxidant in the brain, particularly in the synapse, where it protects against oxidative stress. Ascorbate is released into the synapse as glutamate is cleared from the synapse, an exchange important for excitatory neurotransmission.

Fiona Harrison, PhD, and colleagues investigated the role of ascorbate in susceptibility to seizures. Using genetically-modified mice that, like humans, depend on dietary ascorbate, they report that low ascorbate renders mice more susceptible to pharmacologically-induced seizures and alters the expression of several glutamate transporter genes. Even a single, mild seizure impacted memory in a mouse model for Alzheimer’s disease.

The study published in Neurobiology of Aging supports the importance of brain ascorbate levels in protecting against seizures and cognitive decline in Alzheimer’s disease.

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