Investigating the differential effects of LPS toward cardiac mitochondria in young and aged mice

概述：衰老是涉及生物系统（如线粒体结构和功能）逐渐衰退的自然过程。一生中许多外源性因素会影响线粒体质量，包括暴露于环境毒素，如脂多糖（LPS）。据预测，随着年龄的增长，线粒体损伤的易感性会增加。然而，慢性应激源对线粒体质量的影响以及随后的衰老影响尚不清楚。我的研究兴趣是研究心脏内的长链n-3和n-6多不饱和脂肪酸（PUFA）。这些脂肪酸是磷脂膜的必需成分，是一大家族类二十烷的前体。n-3和n-6 PUFA的代谢通过三个主要的酶系统-环氧化酶（COX），脂氧化酶（LOX）和细胞色素P450 （CYP）酶产生大量的生物活性类二十烷酸。许多类二十烷酸是在炎症反应中产生的；然而，许多这些代谢物的生物活性，特别是在心脏内，在很大程度上仍未被探索和未知。我们的初步数据表明，脂多糖会增加cypp衍生的亚油酸代谢物的产生，从而降低线粒体质量。

OVERVIEW: Aging is a natural process involving the progressive decline in biological systems, such as mitochondrial structure and function. Many exogenous factors over a lifetime can impact mitochondria quality including exposure to environmental toxins like lipopolysaccharide (LPS). It is predicted there is an increased susceptibility to mitochondrial damage with age. However, the effect of chronic stressors on mitochondrial quality and the subsequent impact of aging is unknown. My research has been interested in studying long-chain n-3 and n-6 polyunsaturated fatty acids (PUFA) within the heart. These fatty acids are required components of phospholipid membranes and serve as precursors to a large family of eicosanoids. The metabolism of n-3 and n-6 PUFA occurs through three primary enzymatic systems cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 (CYP) enzymes generating a plethora of bioactive eicosanoids. Many of the eicosanoids are produced in response to inflammation; however, the biological activity of many of these metabolites, notably within the heart, remains largely unexplored and unknown. Our preliminary data suggest LPS triggers increased production CYP-derived metabolites of linoleic acid, which decrease mitochondrial quality. OBJECTIVES: The objective of my NSERC program is to discover novel and fundamental roles for bioactive lipid mediators produced endogenously within the heart. The focus of the current proposal is to explore the effect of low-grade chronic inflammation caused by LPS toward cardiac mitochondrial quality and how this changes in an aged heart. We propose that increased production of detrimental lipid mediators play a critical role in regulating mitochondrial quality contributing to an aged cardiac phenotype. The proposed research will (1) establish the time course and characterization of an eicosanoid profile, mitochondrial quality and cardiac function in young and aged mice exposed to chronic low doses of LPS; (2) evaluate the role of bioactive lipid mediators in regulating mitochondrial quality; and (3) explore the effect of a germ-free environment on cardiac function and mitochondrial during aging. Axenic (germ-free) mice together with a germ-free environment will be utilized to dissect out interactions between the host and LPS. This approach will allow us to explore basic mechanisms of how environmental toxins impact eicosanoid profiles and mitochondrial quality as well some fundamental insight into unique processes of biological aging isolated from microflora. SIGNIFICANCE: This work will increase our knowledge of endogenously produced lipid mediators and identify novel roles they have in regulating mitochondria in young and aged hearts. As well provide insight into understanding how chronic low-grade inflammation will alter eicosanoid profiles and effect mitochondria while investigating the impact of aging.