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

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…Cardiomyocytes lacking Sirt-3 show age-dependent mitochondrial swelling and accelerated signs of cardiac aging, including myocardial hypertrophy and accumulated fibrotic tissue [ 254 ]. Interestingly, while the cardiac expression of sEH is significantly increased in cardiac aging, the genetic deletion of sEH attenuated the age-related decrease in Sirt-3 activity in female mice [ 255 ]. The effect was associated with higher levels of active mitochondrial MnSOD resulting in better overall cardiac function, suggesting the preservation of mitochondrial integrity in aged mice [ 255 ].…”

“…Interestingly, while the cardiac expression of sEH is significantly increased in cardiac aging, the genetic deletion of sEH attenuated the age-related decrease in Sirt-3 activity in female mice [ 255 ]. The effect was associated with higher levels of active mitochondrial MnSOD resulting in better overall cardiac function, suggesting the preservation of mitochondrial integrity in aged mice [ 255 ]. This data fosters an important body of research on the underlying mechanisms involved in the effects of epoxylipids on mitochondrial redox apparatus in cardiac aging and age-related pathogenesis.…”

“…In view of the fact that mitochondria are strongly associated with age-related cardiac differences, comparable mitochondrial sex-differences appear to be a promising theory to explain sex-specific differences in cardiac aging. Sexual dimorphism has been documented in protein expression and regulation of sEH activity in both cardiac and extra-cardiac tissues [ 255 , 268 , 269 , 270 ]. While sEH inhibition did not have discernable effects on female mouse systolic blood pressure (SBP), genetic deletion of sEH efficiently normalized SBP in male mice [ 270 ].…”

“…Sexual disparity in regulating sEH activity becomes more pronounced in aged tissues, as aging is associated with a significant increase in sEH in male animals. This raises new questions on the mechanisms associated with sex-specific responses to sEH-based interventions [ 255 , 268 ].…”

A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway

“…SIRT3 activity was detected in the isolated mitochondrial fractions using a SIRT3 fluorescent assay kit (50088, BPS Bioscience, San Diego, CA, United States), according to the manufacturer's instructions [91]. In this assay, heart mitochondrial fractions were mixed with the specific HDAC fluorogenic substrate, bovine serum albumin, NAD + and assay buffer.…”