The Cardiovascular Complications and Diabetes Program Project (P01HL092969) is funded by the National Heart, Lung, and Blood Institute of the NIH. This Program Project Grant (PPG) was established in 1958 with Dr. Robert H. Williams as Program Director. Dr. Edwin L. Bierman created the focus on lipids, lipoproteins, and cardiovascular disease associated with diabetes when he became Director of the PPG in 1975. Dr. Alan Chait served as Program Director from 1995 to 2012, when Dr. Karin E. Bornfeldt took over the directorship of the Program.
Cardiovascular disease caused by lesions of atherosclerosis in the blood vessel wall is the most devastating complication of diabetes and metabolic syndrome, increasing the risk of heart attack or stroke. The objective of this PPG is to identify cellular and molecular mechanisms of the increased cardiovascular complications associated with diabetes that may be amenable to preventive and therapeutic measures. The overall hypotheses of the PPG are that dysfunctional high-density lipoprotein (HDL) increases the risk of cardiovascular disease in diabetes and the metabolic syndrome, and that the increased glucose, triglycerides and systemic inflammation that characterize diabetes and the metabolic syndrome reduce HDL’s cardioprotective properties. The expertise of our team in different areas relating to cardiovascular disease associated with diabetes and HDL ensures synergy and cross-fertilization among projects, which are likely to markedly advance research and identify new drug targets to combat cardiovascular complications of diabetes and metabolic syndrome.
Development of a lesion of atherosclerosis throughout a blood vessel
Section of a blood vessel (the brachiocephalic artery) from a mouse with atherosclerosis. Formation of a lesion of atherosclerosis begins as an accumulation of immune cells (macrophages – stained light purple) in the blood vessel wall (left). The normal vascular wall consists of smooth muscle cells (red) held together by elastin filaments (black) and is lined by a single layer of endothelial cells (which cannot be seen). Further up the blood vessel, the lesion has developed to a more advanced stage, with accumulation of chondrocyte-like cells believed to be involved in calcification of the lesion (middle). Even further up the blood vessel, the lesion shows signs of a necrotic core (caused by dead and dying macrophages), calcification, accumulation of cholesterol in structures called cholesterol clefts, and bleeding in the lesion (intraplaque hemorrhage). Smooth muscle cells have started to cover the macrophage-rich part of the lesion and formed a fibrous cap (right). These advanced atherosclerotic lesions are believed to contribute to cardiovascular events, such as heart attack and stroke. The Program Project focuses on identifying which processes are accelerated by diabetes and the causative factors. Images courtesy of the laboratory of Karin Bornfeldt, PhD.
The Program consists of four different projects and three core units.
Project 1: HDL Function and Oxidation in Diabetic Atherosclerosis – Jay W. Heinecke, MD, Project Leader
The long-term goal of this project is to identify specific pathways that alter HDL’s functionality in humans with diabetes, which should provide new insights into HDL’s ability to prevent cardiovascular disease. The proposed research is also likely to be helpful in the development of new clinical assays that assess the risk of diabetic cardiovascular disease.
Project 2: Dyslipidemia and Atherosclerosis Regression – Ira J. Goldberg, MD, Project Leader, Edward A. Fisher, MD, PhD, Project Co-Investigator
This project investigates how alterations in triglyceride metabolism impact HDL function and regression of atherosclerosis, and whether hyperglycemia and hypertriglyceridemia are synergistic for creating dysfunctional HDL. Increased understanding in this area will define the factors that affect HDL function and will establish the mechanistic basis of how triglycerides are a cardiovascular risk factor.
Project 3: Adipose Tissue Inflammation and HDL Function – Alan Chait, MD, Project Leader
This project investigates the hypotheses that the inflammation of adipose tissue that accompanies visceral obesity in the metabolic syndrome is due, at least in part, to impaired HDL function, and that dysfunctional HDL is instrumental in causing low-grade inflammation, which increases the risk of cardiovascular disease. This project provides new insights into HDL by focusing on how adipose tissue inflammation, and particularly HDL’s serum amyloid A content, affects HDL function.
Project 4: Diabetes-Induced Myeloid Cell Activation, HDL, and Atherosclerosis – Karin E. Bornfeldt, PhD, Project Leader
This project is centered on understanding how diabetes activates myeloid cells (such as monocyte and macrophages) and thereby promotes atherosclerosis, and also investigates if dysfunctional HDL associated with diabetes is less able to suppress this inflammatory activation of myeloid cells. The long-term goal of this project is to reveal new drug targets for diabetic vascular disease.
Synergy within the Program Project. The PPG’s overall theme is that diabetes and the metabolic syndrome increase cardio-vascular disease (CVD) risk by creating dysfunctional HDL that can no longer effectively protect the artery wall and adipose tissue from cholesterol overload and inflammation. The PPG takes advantage of the expertise and synergy among the four projects and cores to address three components – inflammation (Projects 2, 3 & 4), hypertriglyceridemia (Projects 1 & 2), and hyperglycemia (all projects) – and determine how these components negatively impact HDL functionality (all projects).
Core A: Administrative Core – Karin E. Bornfeldt, PhD, Core Director, Alan Chait, MD, Co-Director
This core directs the overall program, evaluates scientific progress, facilitates interactions among investigators, arranges visits by consultants and Advisory Committees, helps to provide an outstanding training environment for PPG trainees, and provides administrative support.
Core B: Quantitative and Functional HDL Core – Tomas Vaisar, PhD, Core Director
This core provides state-of-the-art mass spectrometry and data analysis for all four projects, isolates HDL, and provides quantitative measures of HDL protein cargo, HDL particle number, and HDL’s cholesterol efflux capacity.
Core C: Tissue and Imaging Core – Kevin D. O’Brien, MD, Core Director
This core provides each of the projects with qualitative and quantitative measures of atherosclerosis, as well as state-of-the-art histological and immunohistochemical support of arterial tissue, liver, adipose tissue, and intestine. It also offers laser-capture microdissection (to analyze gene expression changes in lesion macrophages).