Dr. Ira J. Goldberg and Dr. Ravichandran Ramasamy shed new insight on heart disease in people who have diabetes.
Photo: 嘿嘿视频 Staff
In a long-running collaboration between 嘿嘿视频 endocrinology and cardiology, researchers are shedding light on the molecular factors that prevent atherosclerosis regression in patients with diabetes, closing a major gap in the study of diabetic vascular pathology.
The Impact of Diabetes on Arterial Self-Repair
Two-thirds of people with diabetes die from cardiovascular disease or stroke, and strategies that typically lower low-density lipoproteins (LDL) and reduce atherosclerosis in patients are much less effective in individuals with diabetes. While most of the available research has focused on understanding the underlying mechanisms driving the progression of atherosclerosis in patients, a multidisciplinary team of 嘿嘿视频 researchers has taken a different approach.
鈥淲e are trying to understand the factors that affect atherosclerosis regression,鈥 says Ira J. Goldberg, MD, the Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology and director of the . By regression, Dr. Goldberg and his colleagues mean the reduction in cholesterol and inflammatory cells in the artery that accompanies cholesterol reduction in the blood. These changes are thought to make the artery more stable and less likely to cause a blood clot leading to a heart attack.
鈥淲e are trying to understand the factors that affect atherosclerosis regression,鈥 says Ira J. Goldberg, MD, the Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology and director of the Division of Endocrinology, Diabetes, and Metabolism.
Atherosclerosis, caused by lipoprotein retention within the arterial wall and inflammation associated with macrophage accumulation, is accelerated in people with type 1 and type 2 diabetes, likely due to multiple metabolic abnormalities including dyslipidemia and hyperglycemia. For several years, Dr. Goldberg has been working with Edward A. Fisher, MD, PhD, MPH, the Leon H. Charney Professor of Cardiovascular Medicine, to understand how diabetes impairs the blood vessels鈥 capacity for self-repair after cholesterol has been reduced to normal levels.
鈥淲e are seeking to understand how the abnormal factors in people with diabetes prevent circulating blood cells in blood vessels from becoming reparative,鈥 says Dr. Goldberg. The studies will help to elucidate the link between diabetes and cardiovascular disease.
Tracking Atherosclerosis at the Molecular Level
At the center of the team鈥檚 research is the glucose-metabolizing enzyme aldose reductase, which is thought to fuel diabetes complications by directing glucose into pathways producing inflammatory metabolites. Previous animal models provided little insight into the role that aldose reductase plays in plaque buildup and regression because mice naturally express very low levels relative to humans. Drs. Goldberg and Fisher, along with , professor of medicine and biochemistry and molecular pharmacology, are homing in on the enzyme鈥檚 actions under hyperglycemic conditions.
In earlier studies of diabetic mice, the research team demonstrated that hyperglycemia impairs atherosclerosis regression even in the context of aggressive lipid management. They reported that under hyperglycemic conditions in the body, the number of monocytes drawn to arterial plaques increased in response to lipid lowering, as did the levels of inflammation-promoting macrophages derived from these monocytes. Under hyperglycemic conditions, glucose is not always targeted to energy metabolism but is instead metabolized into harmful metabolites via aldose reductase and likely other enzymes.
The 嘿嘿视频 team created a mouse model that is both diabetic and expresses aldose reductase at human levels, to determine if this exacerbated the negative effects observed in the previous studies. 鈥淚ndeed, we found that if you overexpress aldose reductase in hyperglycemic mice, it totally prevents regression. This suggests that if sugar is aberrantly modified, repair cannot occur,鈥 says Dr. Goldberg.
In fact, the researchers saw continued progression of plaque buildup, despite normal lipid levels, as well as greater macrophage inflammation. These studies also suggest a generalized defect in repair that might underlie other complications of diabetes.
If these mouse models are confirmed to reflect the same metabolic phenomena in humans, investigators expect that the new generation of high-potency aldose reductase inhibitors currently undergoing preclinical testing will show cardiovascular benefits. 鈥淏ecause statins are not as efficacious in people with diabetes, AR-inhibitors could serve as an adjunct therapy, blocking the glucose-specific mechanism that amplifies cardiovascular disease in this population,鈥 says Dr. Ramasamy.
