Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway

Ashrafian, Houman; Czibik, Gabor; Bellahcene, Mohamed; Aksentijević, Dunja; Smith, Anthony C.; Mitchell, Sarah J.; Dodd, Michael S.; Kirwan, Jennifer; Byrne, Jonathan; Ludwig, Christian; Isackson, Henrik; Yavari, Arash; Støttrup, Nicolaj Brejnholt; Contractor, Hussain; Cahill, Thomas J.; Sahgal, Natasha; Ball, Daniel R.; Birkler, Rune Isak Dupont; Hargreaves, Iain P.; Tennant, Daniel A.; Land, John M.; Johannsen, Mogens; Kharbanda, Rajesh K.; Neubauer, Stefan; Redwood, Charles; Cabo, Rafael de; Ahmet, Ismayil; Talan, Mark I.; Günther, Ulrich L.; Robinson, Alan J.; Viant, Mark R.; Pollard, Patrick J.; Tyler, Damian J.; Watkins, Hugh

doi:10.1016/j.cmet.2012.01.017

Cited by 238 publications

(199 citation statements)

References 59 publications

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“…Other experimental studies also showed cellular accumulation of succinate during hypoxia in rabbits7 and on ischemia in the isolated, perfused mouse heart 8. In the current study, we report that cardiac‐specific release of succinate is a feature of human IRI in patients undergoing emergency PPCI for STEMI, most likely reflecting succinate accumulation during ischemia and subsequent release from ischemic myocardial tissue following reperfusion.…”

Section: Discussionsupporting

confidence: 68%

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Kohlhauer

Dawkins

Costa

et al. 2018

JAHA

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BackgroundIschemia–reperfusion injury following ST‐segment–elevation myocardial infarction (STEMI) is a leading determinant of clinical outcome. In experimental models of myocardial ischemia, succinate accumulation leading to mitochondrial dysfunction is a major cause of ischemia–reperfusion injury; however, the potential importance and specificity of myocardial succinate accumulation in human STEMI is unknown. We sought to identify the metabolites released from the heart in patients undergoing primary percutaneous coronary intervention for emergency treatment of STEMI.Methods and ResultsBlood samples were obtained from the coronary artery, coronary sinus, and peripheral vein in patients undergoing primary percutaneous coronary intervention for acute STEMI and in control patients undergoing nonemergency coronary angiography or percutaneous coronary intervention for stable angina or non‐STEMI. Plasma metabolites were analyzed by targeted liquid chromatography and mass spectrometry. Metabolite levels for coronary artery, coronary sinus, and peripheral vein were compared to derive cardiac and systemic release ratios. In STEMI patients, cardiac magnetic resonance imaging was performed 2 days and 6 months after primary percutaneous coronary intervention to quantify acute myocardial edema and final infarct size, respectively. In total, 115 patients undergoing acute STEMI and 26 control patients were included. Succinate was the only metabolite significantly increased in coronary sinus blood compared with venous blood in STEMI patients, indicating cardiac release of succinate. STEMI patients had higher succinate concentrations in arterial, coronary sinus, and peripheral venous blood than patients with non‐STEMI or stable angina. Furthermore, cardiac succinate release in STEMI correlated with the extent of acute myocardial injury, quantified by cardiac magnetic resonance imaging.ConclusionSuccinate release by the myocardium correlates with the extent of ischemia.

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Section: Discussionsupporting

confidence: 68%

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Kohlhauer

Dawkins

Costa

et al. 2018

JAHA

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“…The Krebs, or citric acid, cycle occurs at the junction between glycolysis and oxidative phosphorylation (8) and is a key component of aerobic metabolism by providing reducing equivalents for the electron transport chain. Interestingly, succinate has been known for many years to increase in tissues during hypoxia (9)(10)(11) and may act as a surrogate marker for reduced oxygenation. Accordingly, Sucnr1 may be activated in times of hypoxic stress such as ischemic injury in liver (12) or retina (13) or during cardiomyocyte crisis (14).…”

mentioning

confidence: 99%

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

et al. 2014

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A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1 2/2 mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1 2/2 mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1 2/2 mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1 2/2 mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.

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“…Fumarate is an intermediate formed by the oxidation of succinate. Fumarate has a cytoprotective effect via activation of Nrf2 with the upregulation of protective antioxidant response element genes, by modification of the negative regulator KEAP 1 (Adam et al., 2011; Ashrafian et al., 2012). Temporal measurement of retinal fumarate showed that the content was significantly increased by IF and 3HB‐r compared with that in the AL group (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

et al. 2017

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SummaryCalorie restriction (CR) being the most robust dietary intervention provides various health benefits. D‐3‐hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose‐6‐phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45‐related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

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Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway

Cited by 238 publications

References 59 publications

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

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