BackgroundThere is overwhelming evidence that dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs), mainly EPA (C20:5n-3) and DHA (C22:6n-3), has cardiovascular protective effects on patients with type 2 diabetes mellitus (T2DM) but not on healthy people. Because the T2DM heart increases fatty acid oxidation (FAO) to compensate for the diminished utilization of glucose, we hypothesize that T2DM hearts consume more n-3 PUFAs and, therefore, need more n-3 PUFAs. In the present study, we investigated the changes in cardiac n-3 PUFAs and peroxisomal beta-oxidation, which are responsible for the degradation of PUFAs in a high-fat diet (HFD) and low-dose streptozotocin- (STZ) induced type 2 diabetic rat model.Methods and resultsThe capillary gas chromatography results showed that all the n-3 (or omega-3) PUFAs, especially DHA (~50%) and EPA (~100%), were significantly decreased, and the n-6/n-3 ratio (~115%) was significantly increased in the hearts of diabetic rats. The activity of peroxisomal beta-oxidation, which is crucial to very-long-chain and unsaturated FA metabolism (including DHA), was significantly elevated in DM hearts. Additionally, the real-time PCR results showed that the mRNA expression of most peroxisomal beta-oxidation key enzymes were up-regulated in T2DM rat hearts, which might contribute to the reduction of n-3 (or omega-3) PUFAs.ConclusionIn conclusion, our results indicate that T2DM hearts consume more n-3 PUFAs, especially DHA and EPA, due to exaggerated peroxisomal beta-oxidation.

A bdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the remodeling of the aortic wall, and it frequently leads to high morbidity and mortality because of vascular dissection and rupture.1 Although AAA formation is a multifactorial process involving the infiltration of macrophages, release of proinflammatory cytokines and proteases, elastin breakdown, vascular smooth muscle cell (VSMC) apoptosis, and increased collagen turnover, macrophages are essential contributors to the pathogenesis of AAAs.2,3 Accordingly, monocytes/macrophages are reportedly activated by chronic inflammatory states, including atherosclerosis and oxidative stress, and by angiotensin II (Ang II) and inflammatory cytokines.Subsequently, macrophages infiltrate vessel walls, release proteases such as elastase, matrix metalloproteinase-12 (MMP-12) and metalloproteinases, and degrade extracellular matrix components such as collagen and elastin. 4,5 Simultaneously, infiltrating macrophages secrete inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon-γ, interleukin-1β, and interleukin-6, into the media and adventitia of aneurysmatic vessels, thereby, exacerbating inflammatory responses. 6Macrophage infiltration into vessel walls requires highly coordinated reorganization of actin cytoskeletal structures to create membrane protrusions called podosomes. 7 Human and murine podosomes contain many of the structural components

BackgroundLipotoxicity contributes to diabetic myocardial disease. In this study, we investigated the lipid species contributing to lipotoxicity and the relationship with peroxisomal β-oxidation in the heart of diabetic mice.MethodsMale C57BL/6 mice were randomly divided into a Diabetic group (intraperitoneal injection of STZ) and a Control group (saline). Cardiac function indexes [ejection fraction (EF%) and fractional shortening (FS%)] were evaluated by echocardiography. Morphological changes in the myocardial tissues and mitochondria were assessed by electron microscopy following hematoxylin and eosin staining. Blood myocardial injury indexes and lipids were measured using an automatic biochemical analyzer. Cardiac ATP levels were analyzed using a commercially available kit. mRNA levels of glucose transporter 4 (GLUT4), fatty acid binding protein 3 (FABP3), palmitoyl transferase 1α (CPT-1α), acyl-CoA oxidase 1 (AOX1), D-bifunctional protein (DBP), 3-ketoacyl-CoA thiolase A (THLA), uncoupling protein (UCP) 2 and UCP3 were investigated by quantitative reverse-transcription polymerase chain reaction. FABP3 protein expression was analyzed by Western blotting. Non-targeted metabolomics by LC-MS/MS was applied to evaluate profile of lipid metabolism in heart.ResultsCompared with controls, EF% and FS% were significantly reduced in diabetic mice. Furthermore, blood myocardial injury indexes and lipids, as well as myocardial mitochondrial cristae fusion were significantly increased. In the diabetic heart, GLUT4 expression was decreased, while expression of FABP3, CPT-1α, AOX1, DBP, THLA, UCP2 and UCP3 was increased, and ATP levels were reduced. In total, 113 lipids exhibited significant differential expression (FC > 2, P < 0.05) between the two groups, with sphingolipid metabolism identified as the top-ranking affected canonical pathway. In the diabetic heart, long-chain hydroxyl-acylcarnitines (8/8) and acylcarnitines (6/11), triglycerides (2/5), and diacyglycerol (3/7) were upregulated, while very long-chain polyunsaturated fatty acids (PUFAs) (5/6) including eicosapentaenoate, docosahexaenoate, phosphocholine (11/19), lysophosphocholine (5/9), phosphoethanolamine (7/11), lysophosphoethanolamine (7/10), phosphatidylglycerol (6/8), phosphoserine (6/8), phosphatidylinositol (2/2), phosphatidic acid (1/1), lysophosphatidic acid (1/1) and sphingomyelin (6/6) were downregulated.ConclusionsOur data suggest that the increase in toxic lipid species and decreased in PUFAs undergoing peroxisomal β-oxidation, combined with the reduction in phospholipids cause mitochondrial injury and subsequent uncoupling of phosphorylation and ATP deficiency; thereby leading to diabetic heart dysfunction.