Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

Mohamed Al-Shabrawey; Ahmed Elmarakby; Yara Samra; Mohamed Moustafa; Stephen W Looney; Krishna Rao Maddipati; Amany Tawfik

doi:10.53388/2022-0106-103

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

Life Res (Auckl). 2022 Apr;5(2):14. doi: 10.53388/2022-0106-103.

Authors

Mohamed Al-Shabrawey^{1

2}, Ahmed Elmarakby^{3

4}, Yara Samra^{3

5}, Mohamed Moustafa^{1

2}, Stephen W Looney⁶, Krishna Rao Maddipati⁷, Amany Tawfik^{1

2}

Affiliations

¹ Department of Foundational Medical Studies and Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA.
² Eye Research Institute, Oakland University, Rochester, Michigan, USA.
³ Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
⁴ Departments of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
⁵ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt.
⁶ Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
⁷ Bioactive Lipids Research Program, Department of Pathology, Wayne State University, Michigan, USA.

Abstract

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.

Keywords: cycloxygenase; cystathionine β-synthase; cytochrome-P450; eicosanoids; homocysteine; lipoxygenase.

Abstract

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