Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential

Abstract

Sepsis still causes death, often through cardiac failure and mitochondrial dysfunction. Dietary ω3 polyunsaturated fatty acids are known to protect against cardiac dysfunction and sepsis lethality. This study set out to determine whether early low-severity sepsis alters the cardiac mitochondrial function in animals fed a Western-type diet and whether dietary eicosapentaenoic acid (EPA) administration protects the myocardium against the deleterious effects of sepsis and if so to seek possible mechanisms for its effects. Rats were divided into two groups fed either an ω3 PUFA-deficient diet (“Western diet,” DEF group) or an EPA-enriched diet (EPA group) for 5 weeks. Each group was subdivided into two subgroups: sham-operated rats and rats subjected to cecal ligation and puncture (CLP). In vivo cardiac mechanical function was examined, and mitochondria were harvested to determine their functional activity. Oxidative stress was evaluated together with several factors involved in the regulation of reactive oxygen species metabolism. Sepsis had little effect on cardiac mechanical function but strongly depressed mitochondrial function in the DEF group. Conversely, dietary EPA greatly protected the mitochondria through a decreased oxidative stress of the mitochondrial matrix. The latter was probably due to an increased uncoupling protein-3 expression, already seen in the sham-operated animals. CLP rats in the EPA group also displayed increased mitochondrial sirtuin-3 protein expression that could reinforce the upholding of oxidative phosphorylation. Dietary EPA preconditioned the heart against septic damage through several modifications that protect mitochondrial integrity. This preconditioning can explain the cardioprotective effect of dietary EPA during sepsis.

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice

“…Supplementation of omega-3 fatty acids specifically induces cardiac UCP 3 expression, and overexpression protects cardiomyocytes through reduced ROS generation and apoptosis from I/R injury cardiomyocyte dysfunction and preventing cardiomyocyte death, all involved in the development of LV dysfunction [59][60][61][62]. The induced UCP 3 mRNA expression seen in the myocardium of DHA supplementation sham mice is congruent with in vitro and in vivo studies potentially preventing MI-induced oxidative stress [63][64][65]. The fact that UCP 3 expression decreases after I/R injury in DHA-pretreated mice is surprising, but downregulation of UCP 3 has been reported after I/R injury through the nuclear transcription factor peroxisome proliferator-activated receptor-(PPAR-) α [66,67].…”

Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals

“…Following Ponceau imaging, membranes re-activated in methanol, blocked with nonfat milk for 1 hour (5% w/v diluted in Tri-buffered saline with 0.1% Tween 20, or TBST), washed three times in TBST only (5 minutes per wash), and incubated for 48 hours with the following rabbit anti-[target] IgG antibodies (1:1000 v/v dilution in TBST): i) NAMPT (Abcam; catalog#: Ab45890), ii) SIRT1 (Cell Signaling Technologies; Danvers, MA, USA; catalog#: 9475), iii) SIRT3 (Cell Signaling Technologies; catalog#: 5490), and iv) acetylated lysine (Cell Signaling Technologies; catalog#: 9441). These antibodies have been extensively validated in prior literature: NAMPT [55,56], SIRT1 [57,58], SIRT3 [59,60], acetylated lysine [61,62]. Following primary antibody incubations, membranes were washed three times in TBST only (5 minutes per wash), and incubated for 1 hour with horseradish peroxidase-conjugated antirabbit IgG (Cell Signaling Technologies; catalog#: 7074).…”

Dihydromyricetin Improves Endothelial Dysfunction in Diabetic Mice via Oxidative Stress Inhibition in a SIRT3-Dependent Manner

“…Sirtuin 3 (SIRT3) is the main deacetylase in the mitochondria and serves as a critical mediator in metabolic regulation and antioxidant function [ 22 , 23 , 24 , 25 ]. SOD2, as one target protein of SIRT3, is regulated by SIRT3 via acetylation of lysine residues [ 26 , 27 ].…”