高同型半胱氨酸血症会导致血浆中多不饱和脂肪酸衍生的二十酸水平失调。

Mohamed Al-Shabrawey, Ahmed Elmarakby, Yara Samra, Mohamed Moustafa, Stephen W Looney, Krishna Rao Maddipati, Amany Tawfik
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引用次数: 0

摘要

高同型半胱氨酸血症(HHcy)是导致多种心血管疾病(CVD)发病的原因之一。我们的研究小组之前已经证实,二十烷酸和同型半胱氨酸在糖尿病视网膜病变和肾损伤的血管损伤中起着至关重要的作用。本研究以胱硫醚-β-合成酶杂合小鼠(cβs+/-)为 HHcy 模型,旨在确定同型半胱氨酸对源自多不饱和脂肪酸(PUFA)的脂质介质循环水平的影响。研究人员从野生型(WT)小鼠和 cβs+/- 小鼠体内分离出血浆样本,利用 LC/MS 方法对二十烷酸水平进行评估。与 WT 对照组小鼠相比,cβs+/- 小鼠血浆中 12/15 脂氧合酶(12/15-LOX)活性明显降低。与 WT 对照组相比,cβs+/- 小鼠体内来自欧米伽-3 和欧米伽-6 PUFA 的 LOX 衍生代谢物也有所减少(P < 0.05)。与 LOX 代谢物相反,与 WT 对照组相比,cβs+/- 小鼠体内来自欧米伽-3 和欧米伽-6 PUFA 的细胞色素 P450 (CYP) 代谢物显著升高。环二十碳三烯酸(EETs)是花生四烯酸(AA)经 CYP 代谢产生的环氧化物,具有抗炎特性,已知可限制血管损伤,但其生理作用因被可溶性环氧化物水解酶(sEH)快速降解为相应的二醇(DiHETrEs)而受到限制。与 WT 对照组小鼠相比,cβs+/- 小鼠血浆中 EETs 的生物利用率明显降低,EETs/ DiHETrEs 比率的降低就证明了这一点。cβs+/- 与 WT 对照组小鼠相比,环氧化酶 (COX) 代谢物也明显减少。这些数据表明,HHcy 通过降低 LOX 和 COX 的代谢活性,同时提高 CYP 的代谢活性来影响二十烷酸的代谢。CYP 对 AA 代谢的增加也与 sEH 活性的增加和 EETs 生物利用率的降低有关。二十碳六烷酸代谢失调可能是导致 HHcy 引起心血管疾病的发生和发展的一个因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids.

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids.

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids.

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids.

Hyperhomocysteinemia (HHcy) contributes to the incidence of many cardiovascular diseases (CVD). Our group have previously established crucial roles of eicosanoids and homocysteine in the incidence of vascular injury in diabetic retinopathy and renal injury. Using cystathionine-β-synthase heterozygous mice (cβs+/-) as a model of HHcy, the current study was designed to determine the impact of homocysteine on circulating levels of lipid mediators derived from polyunsaturated fatty acids (PUFA). Plasma samples were isolated from wild-type (WT) and cβs+/- mice for the assessment of eicosanoids levels using LC/MS. Plasma 12/15-lipoxygenase (12/15-LOX) activity significantly decreased in cβs+/- vs. WT control mice. LOX-derived metabolites from both omega-3 and omega-6 PUFA were also reduced in cβs+/- mice compared to WT control (P < 0.05). Contrary to LOX metabolites, cytochrome P450 (CYP) metabolites from omega-3 and omega-6 PUFA were significantly elevated in cβs+/- mice compared to WT control. Epoxyeicosatrienoic acids (EETs) are epoxides derived from arachidonic acid (AA) metabolism by CYP with anti-inflammatory properties and are known to limit vascular injury, however their physiological role is limited by their rapid degradation by soluble epoxide hydrolase (sEH) to their corresponding diols (DiHETrEs). In cβs+/- mice, a significant decrease in the plasma EETs bioavailability was obvious as evident by the decrease in EETs/ DiHETrEs ratio relative to WT control mice. Cyclooxygenase (COX) metabolites were also significantly decreased in cβs+/- vs. WT control mice. These data suggest that HHcy impacts eicosanoids metabolism through decreasing LOX and COX metabolic activities while increasing CYP metabolic activity. The increase in AA metabolism by CYP was also associated with increase in sEH activity and decrease in EETs bioavailability. Dysregulation of eicosanoids metabolism could be a contributing factor to the incidence and progression of HHcy-induced CVD.

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