Age and Sex Differences in Hearts of Soluble Epoxide Hydrolase Null Mice
Age and Sex Differences in Hearts of Soluble Epoxide Hydrolase Null Mice
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DOI：
10.3389/fphys.2020.00048
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发表时间：
2020-02-07
影响因子：
4
通讯作者：
Seubert, John M.
中科院分区：
文献类型：
--
作者：
Jamieson, K. Lockhart;Keshavarz-Bahaghighat, Hedieh;Seubert, John M.
生物老化是生命中不可避免的一部分，几千年来一直吸引着人们。生物系统的逐渐衰退影响心脏功能，并增加对压力的脆弱性，从而导致老年人的发病率和死亡率。然而，我们对衰老的分子、生化和生理机制以及性别差异的理解是有限的。越来越多的证据表明，CYP 450环氧酶介导的n-3和n-6多不饱和脂肪酸（PUFA）代谢产物是调节心脏稳态的活性脂质介质。这些环氧代谢物被可溶性环氧化物水解酶（sEH）快速水解和灭活。目前的研究表征了与相应的野生型（WT）小鼠相比，年轻和老年sEH基因敲除小鼠的心脏功能。除老年雌性sEH基因敲除小鼠外，所有老年小鼠的心脏肥大均显著增加。通过超声心动图评估的心脏功能显示，老龄WT小鼠的心脏功能显著下降，两种性别的射血分数和缩短分数显著降低。有趣的是，与老年WT小鼠相比，老年雌性sEH null小鼠保留了收缩功能，而老年雄性sEH null小鼠保留了舒张功能。对心脏线粒体的评估表明，老年WT男性和女性中乙酰Mn-SOD水平的表达增加与Sirt-3活性的降低相关。相反，与WT小鼠相比，老年sEH无效小鼠保留了Sirt-3活性和更好的线粒体超微结构。与这些变化相一致，WT动物的SOD活性水平显著降低，但在老年sEH无效动物中保持不变。氧化应激标志物显示WT和sEH基因敲除雄性小鼠中蛋白质羰基水平的年龄相关性增加。总之，这些数据突出了来自sEH敲除小鼠的新心脏表型，其显示了心脏中的老化的性二态模式。
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.