Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin

Abstract

Reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are generated in the myocardium in cardiac disease. 4HNE and other toxic aldehydes form adducts with proteins, leading to cell damage and organ dysfunction. Aldehyde dehydrogenases (ALDHs) metabolize toxic aldehydes such as 4HNE into nontoxic metabolites. Both ALDH levels and activity are reduced in cardiac disease. We examined whether reduced ALDH2 activity contributes to cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin (STZ). These mice exhibited most of the characteristics of metabolic syndrome/type-2 diabetes mellitus (DM): increased blood glucose levels depicting hyperglycemia (415.2 ± 18.7 mg/dL vs. 265.2 ± 7.6 mg/dL; P < 0.05), glucose intolerance with normal plasma insulin levels, suggesting insulin resistance and obesity as evident from increased weight (44 ± 3.1 vs. 34.50 ± 1.32 g; P < 0.05) and body fat. Myocardial ALDH2 activity was 60% lower in these mice (0.1 ± 0.012 vs. 0.04 ± 0.015 mmol/min/mg protein; P < 0.05). Myocardial 4HNE levels were also elevated in the hyperglycemic hearts. Co-immunoprecipitation study showed that 4HNE formed adducts on myocardial ALDH2 protein in the mice exhibiting metabolic syndrome/type-2 DM, and they had obvious cardiac hypertrophy compared with controls as evident from increased heart weight (HW), HW to tibial length ratio, left ventricular (LV) mass and cardiomyocyte hypertrophy. Cardiomyocyte hypertrophy was correlated inversely with ALDH2 activity (R2 = 0.7; P < 0.05). Finally, cardiac dysfunction was observed in mice with metabolic syndrome/type-2 DM. Therefore, we conclude that reduced ALDH2 activity may contribute to cardiac hypertrophy and dysfunction in mice presenting with some of the characteristics of metabolic syndrome/type-2 DM when on a high-fat diet and low-dose STZ injection.

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

“…The presence of 13 C from C-3 and C-4 of HNA indicated that this unknown acylCoA contains C-3 and C-4 of HNA. Multiple mass isotopomers of this unknown acyl-CoA with m/z from 908 to 913 were found in livers perfused with [5,5,6,6,7,7,8,8,9,9,9-2 H 11 ]HNE (Fig. 1E).…”

“…HNE and [5,5,6,6,7,7,8,8,9,9, H 11 ]HNE were synthesized as described previously (28 4 . A 0.6 M 4-oxoheptanedioic acid aqueous solution (25 ml) was cooled in ice and mixed with a molar equivalent of NaBD 4 .…”

“…HNE is elevated in oxidative stress-related diseases (3,4). The etiology of HNE as related to disease states is generally ascribed to increasing HNE-modified proteins, DNA, and phospholipids, which has been documented in many diseases, such as cancer (5), diabetes (6,7), obesity (8,9), Alzheimer disease (10,11), atherosclerosis (12,13), etc. High concentrations of HNE and its modified proteins, DNA, and lipids could be due to the increased lipid peroxidation or alternatively the down-regulation of detoxification pathways.…”

“…The detoxification of HNE is generally defined as follows (14 -19): (i) conjugation with glutathione; (ii) reduction to 1,4-dihydroxy-2-nonene (DHN); and (iii) oxidation to 4-hydroxynonenoic acid. Our recent liver perfusions with [5,5,6,6,7,7,8,8,9,9,9-2 H 11 ]HNE revealed that glutathione conjugation with HNE accounts for only ϳ8.7% of total HNE uptake by a perfused rat liver (20), and very little HNE is metabolized to DHN by reduction. Our data indicate that conversion of HNE to 4-hydroxynonanoic acid (HNA) and further catabolism play a dominant role in the detoxification of HNE.…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…The reasons for the impaired activity of ALDH2 are not clear, but it has been recently reported that HNE forms adducts with ALDH2 itself and attenuates its activity (Mali et al. 2014). Surprisingly, mitochondrial NAD + levels and the NAD + /NADH ratio were higher in hearts from fructose‐fed rats.…”