Key result
NLRX1 deletion worsens severe cardiac ischemia-reperfusion injury, increasing infarct size to 73%.
Why the study?
The role of the anti-inflammatory mitochondrial NLRX1 in cardiac ischemia-reperfusion injury and metabolism in the intact heart was unknown.
Absolute Event Rate: 73% vs 63%
p-value: p=<0.05
Deletion of the mitochondrial NLRX1 exacerbates severe cardiac ischemia-reperfusion injury and increases cardiac glucose metabolism in isolated mouse hearts.
NLRX1 modulation merits exploration in cardioprotection; leaves open its relevance beyond isolated mouse hearts to human ischemia-reperfusion injury.
Background NOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart. Methods Isolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13 C-glucose or 0.4 mM 13 C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA). Results NLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption. Conclusion Deletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.
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Zhang et al. (2020) studied Cardiac ischemia-reperfusion injury (n=75). NLRX1 deletion vs. Wild-type (WT) was evaluated on Infarct size following severe (35 min) ischemia and 60 min reperfusion (p=<0.05). Deletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbated severe cardiac ischemia-reperfusion injury, significantly increasing infarct size from 63% to 73%.
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