Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Center for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
Drug Metab Rev. 2013 May;45(2):173-95. doi: 10.3109/03602532.2012.754460.
A plethora of studies have demonstrated the expression of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes in the heart and other cardiovascular tissues. In addition, the expression of these enzymes is altered during several cardiovascular diseases (CVDs), including cardiac hypertrophy (CH). The alteration in CYP and sEH expression results in derailed CYP-mediated arachidonic acid (AA) metabolism. In animal models of CH, it has been reported that there is an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and a decrease in epoxyeicosatrienoic acids (EETs). Further, inhibiting 20-HETE production by CYP ω-hydroxylase inhibitors and increasing EET stability by sEH inhibitors have been proven to protect against CH as well as other CVDs. Therefore, CYP-mediated AA metabolites 20-HETE and EETs are potential key players in the pathogenesis of CH. Some studies have investigated the molecular mechanisms by which these metabolites mediate their effects on cardiomyocytes and vasculature leading to pathological CH. Activation of several intracellular signaling cascades, such as nuclear factor of activated T cells, nuclear factor kappa B, mitogen-activated protein kinases, Rho-kinases, Gp130/signal transducer and activator of transcription, extracellular matrix degradation, apoptotic cascades, inflammatory cytokines, and oxidative stress, has been linked to the pathogenesis of CH. In this review, we discuss how 20-HETE and EETs can affect these signaling pathways to result in, or protect from, CH, respectively. However, further understanding of these metabolites and their effects on intracellular cascades will be required to assess their potential translation to therapeutic approaches for the prevention and/or treatment of CH and heart failure.
大量研究表明细胞色素 P450（CYP）和可溶性环氧化物水解酶（sEH）在心脏和其他心血管组织中表达。此外，这些酶的表达在几种心血管疾病（CVDs）中发生改变，包括心脏肥大（CH）。CYP 和 sEH 表达的改变导致 CYP 介导的花生四烯酸（AA）代谢失调。在 CH 的动物模型中，已经报道 20-羟二十碳四烯酸（20-HETE）增加，环氧二十碳三烯酸（EETs）减少。此外，CYP ω-羟化酶抑制剂抑制 20-HETE 生成和 sEH 抑制剂增加 EET 稳定性已被证明可预防 CH 以及其他 CVDs。因此，CYP 介导的 AA 代谢物 20-HETE 和 EETs 是 CH 发病机制的潜在关键因素。一些研究已经研究了这些代谢物通过其对心肌细胞和血管的作用介导其作用的分子机制，导致病理性 CH。几种细胞内信号级联的激活，如激活的 T 细胞核因子、核因子 kappa B、丝裂原活化蛋白激酶、Rho 激酶、Gp130/信号转导和转录激活物、细胞外基质降解、凋亡级联、炎性细胞因子和氧化应激，与 CH 的发病机制有关。在这篇综述中，我们讨论了 20-HETE 和 EETs 如何分别影响这些信号通路，导致或预防 CH。然而，需要进一步了解这些代谢物及其对细胞内级联的影响，以评估它们在预防和/或治疗 CH 和心力衰竭方面的潜在转化。
