Metabolomics study in patients post myocardial infarction

摘要 这一建议代表了一项在小动物模型中转化我们最新发现的长凳到床边研究 送进诊所。心脏重塑是心脏对外部和内部刺激的普遍反应，包括 压力或容量超负荷，肌节蛋白突变，或心肌收缩质量丧失 心肌梗死(MI)。不利的心脏重构在细胞水平上由心肌细胞肥大、凋亡、 微血管功能障碍、纤维化和电信号紊乱。我们小组是第一个证明 一类新型可溶性环氧化物水解酶(SEH)抑制剂在临床相关模型中的有利作用 心肌肥大和衰竭。SEH是细胞色素P450途径中的一个关键酶。通过以下方式治疗 血管紧张素转换酶抑制剂(SEHIs)预防心肌细胞肥大和电重构 压力超负荷和心肌梗死模型。我们的研究结果进一步证明，使用 SEHIs可预防心脏成纤维细胞的增殖和纤维化。这个项目的重点是新的概念， 细胞色素P450途径的促炎代谢物可通过以下途径导致不利的心脏重构 心肌细胞肥大、凋亡增加，加之细胞因子和 趋化因子导致心脏纤维化的增加。因此，这项提案的主要目标是使用 新的代谢组学研究以确定脂质介质在心脏不良重塑中的机制作用 心肌梗死后的患者。治疗心脏不良重构的新治疗模式可能会产生很大的影响。

ABSTRACT This proposal represents a bench-to-bedside study to translate our recent findings in small animal models into the clinic. Cardiac remodeling is the heart’s prevailing response to extrinsic and intrinsic stimuli including pressure or volume overload, mutations of sarcomeric proteins, or loss of contractile mass from myocardial infarction (MI). Adverse cardiac remodeling is driven at the cellular level by myocyte hypertrophy, apoptosis, microvascular dysfunction, fibrosis, and electrical perturbations. Our group was the first to demonstrate beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. SEH is a critical enzyme in the cytochrome P450 pathway. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and myocardial infarction models. Our findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. This project is focused on the novel concept that pro-inflammatory metabolites of the cytochrome P450 pathway can result in adverse cardiac remodeling by increasing cardiac myocyte hypertrophy, apoptosis, coupled with a persistent increase in cytokines and chemokines leading to an increase in cardiac fibrosis. Hence, the main objective of this proposal is to use novel metabolomic profiling to determine the mechanistic roles of lipid mediators in adverse cardiac remodeling in patients post MI. New treatment paradigms for adverse cardiac remodeling are likely to be highly impactful.