Investigating Methylglyoxal Mediated DNA Damage in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by an increase in blood pressure in the pulmonary arteries. The hypertensive force driving PAH often results in detrimental physiological changes of the pulmonary arteries and right ventricle (RV). This RV remodeling ultimately leads to RV failure and death. As a quickly progressing disease, median survival in PAH is only 5-7 years, with the strongest predictor of mortality being RV dysfunction (RVD). A key indicator of PAH in patients is mitochondrial dysfunction, and the resulting presence of methylglyoxal (MG): a toxic intermediate byproduct of glycolysis. While little is understood of the process, MG intermediates are thought to be able to induce post-translational DNA damage. The effect of MG exposure to differentiating cardiomyoblasts was tested using western blot analysis and immunohistochemistry. The DNA damage was measured using the presence of pH2AX antibodies as a marker for double-stranded DNA breaks. The results of the western blot analyses revealed that cardiomyoblasts exposed to 625µM MG for 4 hours experienced a 9.99 fold increase in pH2AX expression relative to the control (p-value < 0.05). The immunohistochemistry was conducted using both pH2AX and H2AX as markers of DNA damage, and the immunohistochemistry results revealed a positive relationship between MG exposure and DNA damage in cardiomyoblasts. Further research will be necessary in order to more fully delineate the relationship between MG and DNA damage in regards to PAH.