The Progression of DNA Damage in Pulmonary Arterial Endothelial Cells into Pulmonary Arterial Hypertension
Hwang, Soo Kyung
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Hwang, Soo Kyung
As one of the categories of pulmonary hypertension, pulmonary arterial hypertension is a disease that results in high blood pressure in the blood vessels of the lungs. Although there are several treatments available, there is currently no cure to prevent the worsening of the disease over time, and it can be life-threatening from the dangerous accumulation of pressure in the pulmonary arteries. Research from the Rabinovitch lab at Stanford School of Medicine highlights the crucial involvement of DNA damage in pulmonary arterial endothelial cells in the development of pulmonary arterial hypertension. They found that deletion of nuclear receptor PPARγ gene in endothelial cells results in unrepaired DNA damage and worsened pulmonary vasculature characteristic to the disease. As a follow-up, my research attempts to uncover a significant connection between unrepaired DNA damage and the progression of pulmonary arterial hypertension: I propose that the accumulation of unrepaired DNA damage leads to a worsened disease phenotype. To test this, endothelial cell-specific deletion of a DNA damage sensing gene Mre11 in transgenic mice was utilized to induce a condition susceptible to DNA damage. Both wild-type and knock-out mice with endothelial cell-specific deletion of Mre11 were first placed in hypoxic chambers of 8% oxygen for 10 days. I then compared the two groups in the following categories to characterize differences in DNA damage levels and disease severity: hemodynamic measurements of right ventricular systolic pressure (RVSP), left ventricular end diastolic pressure (LVEDP), complete blood count (CBC); quantification of DNA damage; and the number of (muscularized) small pulmonary arteries. Contrary to my expectations, I found a higher trend of RVSP in the wild-type mice, a greater amount of DNA damage in the knock-out mice that was only slightly significant, no significant difference in the number of small pulmonary arteries between the two groups of mice, and a significantly greater amount of fully muscularized small pulmonary arteries in the wild-type mice. These results do not support the notion that DNA damage in pulmonary arterial endothelial cells is a causal factor of the progression of pulmonary arterial hypertension, but the limitations of the experimental design and potential improvements must be considered before coming to a definite conclusion.