Abstract
Whether dietary omega-3 (n-3) polyunsaturated fatty acid (PUFA) confers cardiac benefit in cardiometabolic disorders is unclear. We test whether dietary α-linolenic acid (ALA) enhances myocardial resistance to ischemia-reperfusion (I-R) and responses to ischemic preconditioning (IPC) in type 2 diabetes (T2D); and involvement of conventional PUFA-dependent mechanisms (caveolins/cavins, kinase signaling, mitochondrial function, and inflammation). Eight-week male C57Bl/6 mice received streptozotocin (75 mg/kg) and 21 weeks high-fat/high-carbohydrate feeding. Half received ALA over six weeks. Responses to I-R/IPC were assessed in perfused hearts. Localization and expression of caveolins/cavins, protein kinase B (AKT), and glycogen synthase kinase-3β (GSK3β); mitochondrial function; and inflammatory mediators were assessed. ALA reduced circulating leptin, without affecting body weight, glycemic dysfunction, or cholesterol. While I-R tolerance was unaltered, paradoxical injury with IPC was reversed to cardioprotection with ALA. However, post-ischemic apoptosis (nucleosome content) appeared unchanged. Benefit was not associated with shifts in localization or expression of caveolins/cavins, p-AKT, p-GSK3β, or mitochondrial function. Despite mixed inflammatory mediator changes, tumor necrosis factor-a (TNF-a) was markedly reduced. Data collectively reveal a novel impact of ALA on cardioprotective dysfunction in T2D mice, unrelated to caveolins/cavins, mitochondrial, or stress kinase modulation. Although evidence suggests inflammatory involvement, the basis of this “un-conventional” protection remains to be identified.
Highlights
Dietary n-3 polyunsaturated fatty acids (PUFAs) may confer benefit in metabolic disease [1,2]; effects on homeostasis and disease risk are mixed [3,4]
Trends to increased fasting insulin levels (Figure 1D) in type 2 diabetes (T2D) mice did not reach statistical significance compared to controls prior to acid (DHA) from α-linolenic acid (ALA) supplementation (p =
Membrane microdomain, or mitochondria associated caveolin and cavin levels were modified with ALA, we find no evidence for PUFA-dependent changes in either caveolar levels or translocation to mitochondria, which has been linked to cardioprotection [116]
Summary
Dietary n-3 polyunsaturated fatty acids (PUFAs) may confer benefit in metabolic disease [1,2]; effects on homeostasis and disease risk are mixed [3,4]. Two essential fatty acids cannot be synthesized and must be acquired through the diet—a-linolenic acid (18:3n-3) and linoleic acid (18:2n-6) [2] These are used to synthesize a variety of other unsaturated fatty acids, including the long chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from α-linolenic acid (ALA), and arachidonic acid, from linoleic acid [2]. These may in turn be converted to eicosanoids and prostaglandins, which play important roles in inflammation and inflammatory disorders such as cardiovascular disease [2]. While modulation of inflammation and associated pathways has been implicated in the biological effects of n-3 PUFAs, the mechanistic basis of benefit remains to be detailed
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