GENETIC DELETION OF SOLUBLE EPOXIDE HYDROLASE PRESERVES CARDIAC FUNCTION IN AGED FEMALE MICE

Abstract

Biological aging is an inevitable part of life that has intrigued individuals for millennia. The progressive decline in biological systems impacts cardiac function and increases vulnerability to stress contributing to morbidity and mortality in elderly individuals. Yet, our understanding of the molecular, biochemical and physiological mechanisms as well as sex differences is limited. There is growing evidence indicating CYP450 epoxygenase-mediated metabolites of n-3 and n-6 polyunsaturated fatty acids are active lipid mediators regulating cardiac homeostasis. These epoxy metabolites are rapidly hydrolyzed and inactivated by the soluble epoxide hydrolase (sEH). The current study aims to characterize cardiac function in young and aged sEH null mice compared to the corresponding wild-type (WT) mice. Cardiac function was assessed in both young (3 month) and aged (16 month) WT and sEH null male and female mice by echocardiography. There were no significant differences in cardiac function observed between young WT and sEH null mice. However, there was a marked decline in cardiac function in aged WT mice, notably significant decreases in ejection fraction and fractional shortening in both female and males. Interestingly, female aged sEH null mice demonstrated preserved cardiac function compared to aged WT and sEH null males. As well, the development of left ventricular (LV) mass was lower in aged female sEH null mice compared to other mice. While the etiology of age-related cardiovascular pathogenesis is poorly understood, it has been shown that deterioration of mitochondria over time plays a critical role in age-related cardiac dysfunction. Increased oxidative stress associated with dysfunctional mitochondria correlated with increased expression of both cytosolic and mitochondrial phosphorylated Akt in all aged mice. Increased expression of acetyl Mn-SOD was observed in aged WT and aged male sEH null mice but not aged female sEH null mice. Together these data demonstrated deletion of sEH in aged female mice correlates with preserved cardiac function in mice.