Jamieson K Lockhart, Keshavarz-Bahaghighat Hedieh, Darwesh Ahmed M, Sosnowski Deanna K, Seubert John M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Front Physiol. 2020 Feb 7;11:48. doi: 10.3389/fphys.2020.00048. eCollection 2020.
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.
生物衰老作为生命中不可避免的一部分，已经吸引了人们数千年。生物系统的逐渐衰退会影响心脏功能，并增加对压力的易感性，从而导致老年个体发病和死亡。然而，我们对衰老的分子、生化和生理机制以及性别差异的了解仍然有限。越来越多的证据表明，细胞色素P450环氧合酶介导的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。这些环氧代谢产物会被可溶性环氧化物水解酶（sEH）迅速水解并失活。本研究对年轻和老年sEH基因敲除小鼠与相应野生型（WT）小鼠的心脏功能进行了表征。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，老年WT小鼠明显下降，尤其是两性的射血分数和缩短分数均显著降低。有趣的是，与老年WT小鼠相比，老年雌性sEH基因敲除小鼠保留了收缩功能，而老年雄性sEH基因敲除小鼠保留了舒张功能。对心脏线粒体的评估表明，老年WT雄性和雌性小鼠中乙酰锰超氧化物歧化酶（acetyl Mn-SOD）水平的表达增加，这与Sirt-3活性降低相关。相反，与WT小鼠相比，老年sEH基因敲除小鼠保留了Sirt-3活性，线粒体超微结构也更好。与这些变化一致，SOD的活性水平在WT动物中显著降低，但在老年sEH基因敲除动物中得以保留。氧化应激标志物显示，WT和sEH基因敲除雄性小鼠的蛋白质羰基水平随年龄增长而增加。总之，这些数据突出了sEH基因敲除小鼠的新心脏表型，显示出心脏衰老的性别二态性模式。
