Project 467039

Loss of critical heart cells and the associated reduction in heart contraction are defining features of heart dysfunction in aging and after a serious cardiovascular event. Plasminogen activator inhibitor-1 (PAI-1) is a protein that has a known role in the process of blood clotting. It is well understood that low levels of Pai-1 cause bleeding disorders. Studies in mice lacking Pai-1 show spontaneous cardiac impairment in response to aging. These results are also observed within the Berne Amish community, which has an increase in individuals lacking Pai-1, and they experience accelerated cardiac disease. Metformin is drug administered to patients with diabetes which has a strong safety record and sugar-lowering function. Metformin treatment also improves cardiac impairment and can reduce cardiac damage in response to a form of surgery that causes cardiac stress. Under conditions where levels of Pai-1 are low, cardiac damage increases during aging or under cardiac stress and impairs cardiac healing. Thus, we hypothesize treatment of mice lacking Pai-1 with metformin will reduce cardiac damage and improve heart function. Aim one will investigate if mice lacking Pai-1 treated with metformin have reduced spontaneous development of cardiac damage associated with aging. Aim two will investigate if mice lacking Pai-1 treated with metformin have reduced cardiac damage in response to two models of cardiac stress, (i) a form of surgery and (2) inducing a high blood pressure state. In both aims, heart function will be assessed via ultrasound and damage (scarring) will be assessed using other techniques. These experiments will add significantly to the cardiovascular impact of metformin in a setting of low Pai-1 levels.