My laboratory studies how atherosclerosis—narrowing and hardening of the arteries—occurs. Atherosclerosis leads to abnormalities in blood vessels and eventually affects the flow of blood. When atherosclerosis occurs in the arteries that supply blood to the heart, it can lead to angina and heart attacks. When it occurs in arteries that supply blood to the brain, it can cause transient ischemic attacks (TIAs) and stroke. People who smoke, or have high blood pressure, diabetes, and high cholesterol are at increased risk for atherosclerosis. Our laboratory is studying how these risk factors work to affect the development of atherosclerosis.
 
In particular, we focus on the endothelial cells that line blood vessels. Endothelial cells produce many factors that are important to normal blood vessel function, including nitric oxide (NO), a gas that dilates blood vessels. There is evidence that NO is protective, and a lack of NO may be important in changes that eventually lead to atherosclerosis. We are studying the enzyme that makes NO (eNOS) to see how high cholesterol, diabetes, and obesity affect them. We hope to figure out the precise connections between the risk factors and atherosclerosis so we can devise new ways to treat and prevent heart disease and stroke.
 
Our work to date has demonstrated the importance of NO in endothelial function using disease models in animal systems. We are now focusing on the intersection between metabolic diseases such as obesity and diabetes, and how they affect vascular function and lead to the development of atherosclerosis. Our recent work demonstrates that by altering a key phosphorylation site on eNOS, we can affect the outcome to stroke and reduce stroke size. The implications for our work include new methods for the treatment and prevention of heart attacks, stroke, and high blood pressure.

Our laboratory is generating patient-specific iPS cells to determine whether genetic and environmental factors lead to cell autonomous effects that reproduce human disease phenotypes. One project generates iPS cells from subjects carrying specific genetic variants that coinfer susceptibility or resistance to type 2 diabetes. Our hypothesis is that such iPS cells, when differentiated into pancreatic beta cells, will preserve effects on beta cell function, such as glucose stimulated insulin secretion or growth and apoptosis properties. Another project develops endothelial cells from iPS cells from human subjects with diabetes and coronary artery disease and tests whether endothelial function in culture and in vivo reflect human disease. A third project tests whether cardiac myocytes differentiated from iPS cells from patients who have shown chemotherapy-induced cardiotoxicity will reflect sensitivity to HER2 signaling.

As a practicing cardiologist in the MGH Heart Center, I am Principal Investigator of the translational research CAMP MGH (MGH Cardiology and Metabolic Patient) Cohort. This cohort comprises over 3000 MGH Heart Center subjects with detailed phenotyping, genotyping, and physiologic characterization of glucose tolerance and vascular function (both carotid IMT and brachial artery FMD).

Overall, my laboratory and translational medicine research groups use molecular, genetic, and genomic approaches to study the mechanisms of endothelial dysfunction and atherogenesis, using in vivo models and human studies wherever possible.