Control of Atherosclerosis Regression by PRMT2 in Diabetes
Abstract
Diabetics have more heart disease than their non-diabetic counterparts, even though drugs like Lipitor are equally effective in both groups at lowering the blood levels of harmful cholesterol. We propose to help to understand why comparable reductions in the levels of harmful cholesterol are less effective in diabetics than in their non-diabetic counterparts and to reverse this discrepancy between the two populations. Therefore, this proposal addresses the topic areas of both cardiovascular health and diabetes. We have identified an enzyme called PRMT2, which regulates the abundance of a cellular cholesterol transporter that helps to prevent cells from accumulating in arteries and forming a plaque. When a plaque grows, it blocks the flow of blood through the artery, which makes the heart work harder and can result in a heart attack or a stroke if the plaque dislodges. We have shown that the level of PRMT2, while high in healthy cells, is very low in cells from diabetics when blood sugar levels are elevated. Because PRTM2 isn t around in cells under diabetic conditions, we predict that more cells accumulate in the artery, thus allowing the plaque to grow and exacerbating heart disease in diabetics. To test this proposal, we will determine what happens to the growth of a plaque in an artery when we eliminate PRMT2 with and without diabetes in mouse models of heart disease. We expect that plaques will grow larger in the absence of PRMT2. To better understand how PRMT2 suppresses plaque growth, we will also identify proteins that are modified by PRMT2 in cells from the plaque and determine if these proteins participate in plaque formation. Given that we also don t understand why PRMT2 levels decrease in diabetes, we will identify cellular proteins that regulate PRMT2 levels. That knowledge might enable us to develop ways to restore the normal level of PRMT2 in diabetes and prevent the cells from contributing to plaque formation. This would reduce the risk of heart attack and stroke, especially in diabetics. Applicability of the research: What types of patients will this help? This research will help patients with heart disease, especially those with diabetes where current therapies, like cholesterol-lowering statins, don t seem to work as well as in non-diabetics with elevated levels of harmful cholesterol. What are the potential clinical applications? Clinicians could gain the ability to treat patients with coronary heart disease and diabetes by increasing PRMT2 to lower the risk of heart attack and stroke. Will the study achieve a patient-related outcome? This is a preclinical study that could pave the way for future drug development and clinical trial. It will deliver patient-related outcomes by laying important groundwork to determine how PRMT2 regulates heart disease in diabetes, ultimately enabling future drug treatment that restores PRMT2 levels in diabetes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610374
Entities
People
- Edward A Fisher
Organizations
- Grossman School of Medicine
- United States Army