Age and Sex Differences in Hearts of Soluble Epoxide Hydrolase Null Mice.

K Lockhart Jamieson,John M Seubert,Ahmed M Darwesh,Deanna K Sosnowski,Hedieh Keshavarz-Bahaghighat

doi:10.3389/fphys.2020.00048

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 aged individuals. Yet, our understanding of the molecular, biochemical and physiological mechanisms of aging 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 (PUFAs) are active lipid mediators regulating cardiac homeostasis. These epoxy metabolites are rapidly hydrolyzed and inactivated by the soluble epoxide hydrolase (sEH). The current study characterized cardiac function in young and aged sEH null mice compared to the corresponding wild-type (WT) mice. All aged mice had significantly increased cardiac hypertrophy, except in aged female sEH null mice. Cardiac function as assessed by echocardiography demonstrated a marked decline in aged WT mice, notably significant decreases in ejection fraction and fractional shortening in both sexes. Interestingly, aged female sEH null mice had preserved systolic function, while aged male sEH null mice had preserved diastolic function compared to aged WT mice. Assessment of cardiac mitochondria demonstrated an increased expression of acetyl Mn-SOD levels that correlated with decreased Sirt-3 activity in aged WT males and females. Conversely, aged sEH null mice had preserved Sirt-3 activity and better mitochondrial ultrastructure compared to WT mice. Consistent with these changes, the activity level of SOD significantly decreased in WT animals but was preserved in aged sEH null animals. Markers of oxidative stress demonstrated age-related increase in protein carbonyl levels in WT and sEH null male mice. Together, these data highlight novel cardiac phenotypes from sEH null mice demonstrating a sexual dimorphic pattern of aging in the heart.

Highlights

The prevalence of cardiovascular disease (CVD) has markedly increased as the global population ages (North and Sinclair, 2012; Benjamin et al, 2019)
Both aged male and female WT mice and male soluble epoxide hydrolase (sEH) null mice demonstrated significant increases in heart weight (HW):tibia length (TL); no increases were observed in aged female sEH null mice (Figure 1B)
While the Akt pathway has an important role as a pro-survival pathway, increased activation of Akt over aging has been shown to contribute to age-related cardiac hypertrophy and inflammation (Hua et al, 2011; Chen et al, 2017)

Summary

Introduction

The prevalence of cardiovascular disease (CVD) has markedly increased as the global population ages (North and Sinclair, 2012; Benjamin et al, 2019). Important age-associated changes resulting in structural deterioration and progressive decline in cardiac function is characterized with development of left ventricular hypertrophy, systolic, and diastolic dysfunction and decreased exercise capacity (Chiao and Rabinovitch, 2015). The influence of age on the heart is welldocumented, the sex-specific patterns of cardiac aging in males and females are less appreciated. Sex-associated differences, such as a higher incidence of obstructive diseases in males compared to microvascular complications in females, contribute to the variations in cardiac outcomes persistently observed between men and women (Zhou and Gao, 2010; Keller and Howlett, 2016). Much of the early work into these sex-associated cardiovascular outcomes focused on the role of endogenous hormones as mediators of cardiovascular protection (Huang and Kaley, 2004). Recent data suggest that hormonal changes alone are insufficient to fully explain these variations, and other involved biological mechanisms remain a subject of ongoing debate (Regitz-Zagrosek and Kararigas, 2016)

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