Mechanism of Chemotherapy Induced Microvascular Dysfunction in Cancer Survivors

Project Abstract Every year 255,000 new cases of breast cancer are diagnosed amounting to well over 4,000 deaths occurring per year in U. S alone. With the use of anthracycline-based polychemotherapy (including doxorubicin), the reduction in annual deaths from breast cancer is approximately 38% for women under 40. Systemic Chemotherapy (CTx) plays an important role in the management of these patients; however, most CTx agents have severe adverse consequences on the cardiovascular system. Injury to the heart as a result of exposure to CTx is well established; however, little data exist on the contribution of CTx to endothelial cell dysfunction and the direct effect on mitochondria in the microcirculation. Doxorubicin (DOX), a widely used CTx drug, is known to cause excessive DNA damage, including in the mitochondria where DNA damage increases reactive oxygen species (ROS) production. Mitochondrial dysfunction, induced by mitochondrial DNA (mtDNA) damage, uncouples coronary blood flow from cardiac workload. Excessive mtDNA damage leads to an elevation in cell free (cf) mtDNA which is known to act as a secondary messenger, triggering an inflammatory response in the vascular endothelium. cfmtDNA has been observed in disease models of endothelial dysfunction and correlated with poor clinical outcomes but not investigated on a mechanistic level or in Cardio-Oncology. The restoration of mitochondrial integrity in the coronary microvasculature has proven to be sufficient to restore normal heart function, yet few reports show CTx effect on mitochondrial function, and none have investigated effects in the microvasculature. To date, no studies exist which consider the contribution of mitochondrial function and mtDNA damage on cell survival and physiological endothelial function after CTx in human coronary vessels. We speculate the acute effect of CTx induced mtDNA damage is further amplified by elevation of circulating mtDNA fragments, leading to diminished vascular reactivity. As CTx is known to be more effective at damaging cancerous cells than host and endothelial cells, elevation of mtDNA fragments after effective anticancer therapy is a reasonable expectation. This raises the possibility that CTx-induced endothelial dysfunction may play a key role in development of myocardial pathologies. The focus of this proposal is to define the direct signaling events that mechanistically link CTx to microvascular endothelial damage.