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Activation of DDAH for the Treatment of Atherosclerosis

Institution: Stanford University
Investigator(s): Yohannes Ghebremariam, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20FT-0090 Award: $87,350
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Atherosclerosis (plaque deposition in arteries) is characterized by the build-up of fatty materials such as cholesterol on the walls of blood vessels (arteries) resulting in inflammation and arterial stiffness. Atherosclerosis is a global burden affecting tens of millions of people of all ages. Research has shown that hardening, narrowing and blockage of blood vessels can significantly reduce blood flow and oxygen supply to vital organs of the body and lead to heart attack, stroke, and death. The risk of atherosclerosis is significantly elevated with age, obesity, family history, high blood sugar and lifestyle such as the consumption of high fat diet, lack of exercise and smoking. In particular, tobacco-smoke accelerates plaque deposition in large blood vessels that feed the leg, the brain and the heart increasing the risk of amputation (gangrene), stroke and heart attack in active smokers and these who are exposed to tobacco-smoke through secondhand smoke. According to the American Heart Association (AHA), cigarette smoke is responsible for 440,000 deaths every year in the United States alone and atherosclerosis is one of the principal causes of the deaths that are associated with smoking. In addition, cigarette smoke also increases blood pressure (hypertension) linking the overall increased risk of stroke, heart attack and premature death in smokers who have these conditions compared to non-smokers with high blood pressure. Unfortunately, the existing treatments are less efficient in some patients in lowering fatty deposits or protecting the lining of the blood vessels from being inflamed, hardened or ruptured. Accordingly, there is an urgent need to develop new therapeutic approaches for atherosclerosis.

As mentioned above, one of the causes of atherosclerosis and hypertension is inadequate blood flow that is associated with low levels of a molecule called nitric oxide (NO). NO is produced in different parts of the body and is responsible for maintaining blood pressure and the health of the heart and blood vessels. An inhibitor of NO synthesis, known as asymmetric dimethylarginine (ADMA), when present in the body at abnormal levels, is associated with atherosclerosis and hypertension. Therefore, our goal is to discover new drugs that reduce ADMA levels in the body by increasing the action of an enzyme that breaks down ADMA. This enzyme is known as dimethylarginine dimethylaminohydrolase (DDAH). It has already been shown in animals that increasing the action of DDAH have beneficial effects in reducing plaque deposits in atherosclerosis and maintaining blood pressure. We now aim to discover a drug that can be used to treat patients with atherosclerosis and high blood pressure.

Development of a Dimethylarginine Dimethylaminohydrolase (DDAH) Assay for High-Throughput Chemical Screening
Periodical: Journal of Biomolecular Screening Index Medicus:
Authors: Ghebremariam YT, Erlanson DA, Yamada K and Cooke JP ART
Yr: 2012 Vol: 17 Nbr: 5 Abs: Pg: 651-61