Areas of Research

Environmental Cardiology

One unappreciated and understudied factor contributing to the development or exacerbation of cardiovascular disease is exposure to environmental pollutants. There is a particularly strong association between exposure to airborne particulate matter (PM2.5) and cardiovascular morbidity and mortality.

These particles arise mainly from the combustion of organic materials and are abundant in vehicle exhausts, factory emissions and fires. Using both humans and mice, our group is: 1) trying to identify those adverse outcomes resulting from PM2.5 exposure; and 2) the mechanisms underlying these outcomes.

In prior human studies we have determined that acute PM2.5 exposure led to a depletion of circulating endothelial progenitor cells (EPCs), increases in endothelial microparticles indicating endothelial cell damage, increases in circulating immune cell populations, promoted the production of anti-angiogenic cytokines while suppressing pro-angiogenic growth factors and activated platelets.

In mice we also determined that PM2.5 exposure induced functional defects in bone marrow-resident EPCs and disrupted normal hematopoiesis by reducing the production of neutrophils. These wide ranging outcomes indicate that PM2.5 is effective in inducing endothelial dysfunction and systemic inflammation.

Consequently, these responses could contribute to the development of chronic cardiovascular disease (e.g. atherogenesis), and increase the risk of thrombosis and acute cardiovascular events. In ongoing studies, we are exploring whether the induction of oxidative stress by PM2.5 is the basis for these outcomes and whether we can mitigate these outcomes by limiting the production of reactive oxygen species.

PM2.5 exposures rarely occur is isolation and are often mixed with volatile organic compounds, gases, and metals. Hence in other studies we examined the effects of exposure to benzene on metabolic and cardiovascular outcomes. Similar to the effects of PM2.5, we found that mice inhaling volatile benzene had multiple adverse outcomes including the development of insulin resistance, a depletion of circulating EPCs, a loss of hematopoietic stem cells and platelet activation.

Similar mechanistic and interventional studies are ongoing.

Bone marrow defects in diabetes

Diabetes is rapidly becoming a worldwide epidemic. One of the hallmarks of this disease is the existence or development of a dysfunctional endothelium, which in turn may be attributable to an EPC bone marrow mobilization defect.

Using cell culture and animal models, we have identified a novel mechanism for this mobilization defect. Growth of progenitor cells in hyperglycemia leads to aberrant PKA activation with consequent phosphorylation of the α4 integrin and stable adhesion in the bone marrow.

The limitation of PKA activity or α4 integrin phosphorylation reveres the effects of hyperglycemia and promoted EPC mobilization and wound healing. We are currently developing further insight into this mechanism and exploring if this mechanism is operative in other bone marrow pathologies.