Branched-chain amino acids-induced cardiac protection against ischemia/reperfusion injury

Abstract

Aims: Amino acids, especially branched chain amino acids (BCAAs), have important regulatory roles in protein synthesis. Recently studies revealed that BCAAs protect against ischemia/reperfusion (I/R) injury. We studied the signaling pathway and mitochondrial function affecting a cardiac preconditioning of BCAAs.Main methods: An in vivo model of I/R injury was tested in control, mTOR +/+ , and mTOR +/-. Mice were randomly assigned to receive BCAAs, rapamycin, or BCAAs + rapamycin. Furthermore, isolated cardiomyocytes were subjected to simulated ischemia and cell death was quantified.Biochemical and mitochondrial swelling assays were also performed. Key findings: Mice treated with BCAAs had a significant reduction in infarct size as a percentage of the area at risk compared to controls (34.1 ± 3.9% vs. 44.7 ± 2.6%, P = 0.001), whereas mice treated with the mTOR inhibitor rapamycin were not protected by BCAA administration (42.2 ± 6.5%, vs. control, P = 0.015). This protection was not detected in our hetero knockout mice of mTOR. Western blot analysis revealed no change in AKT signaling whereas activation of mTOR was identified. Furthermore, BCAAs prevented swelling which was reversed by the addition of rapamycin. In myocytes undergoing simulated I/R, BCAA treatment significantly preserved cell viability (71.7 ± 2.7% vs. 34.5 ± 1.6%, respectively, p < 0.0001), whereas rapamycin prevented this 4 BCAA-induced cardioprotective effect (43.5 ± 3.4% vs. BCAA, p < 0.0001).Significance: BCAA treatment exhibits a protective effect in myocardial I/R injury and that mTOR plays an important role in this preconditioning effect.

Leucine Imparts Cardioprotective Effects by Enhancing mTOR Activity and Mitochondrial Fusion in a Myocardial Ischemia/reperfusion Injury Murine Model

“…[26] Previously, we demonstrated that BCAAs show cardioprotective effects via the mTOR signaling pathway. [12] In this study, Leu reduced infarct size in wild-type mice, but not in mTOR +/− mice. Therefore, this result indicates that Leu is the key amino acid that stimulates mTOR activity and protects the heart from I/R injury.…”

“…[9] [10] [11] Recently, we showed the cardiac preconditioning effect of branched-chain amino acid (BCAA) treatment on I/R injury in mice, resulting from increased mammalian target of rapamycin (mTOR) activity and improved mitochondrial function. [12] Among BCAAs, leucine (Leu) can activate mTOR kinase, thereby leading to the phosphorylation of p70S6 kinase and increasing the phosphorylation of serine residues in insulin receptor substrate-1 [13], which inhibits insulin signaling and insulin-stimulated glucose transport in muscles and fats. However, whether Leu has cardioprotective effects on diabetic hearts is unclear.…”

Effects of Remimazolam and Propofol on Ca2+ Regulation by Ryanodine Receptor 1 with Malignant Hyperthermia Mutation

“…Membranes were blocked in 20 mM Tris-buffered saline (TBS) plus Tween (0.1%) containing 2% skim milk and incubated with monoclonal primary antibodies (RYR1 (D4E1), #8153, Cell Signaling Technology, Danvers, MA, USA) overnight at 4°C. Immunolabeled blots were visualized using horseradish peroxidase-conjugated secondary antibodies (Santa Cruz Biotechnology, Dallas, TX, USA) and visualized using an enhanced chemiluminescence reagent (Bio-Rad Laboratories) [ 13 ].…”

PHLDA3 inhibition attenuates endoplasmic reticulum stress‑induced apoptosis in myocardial hypoxia/reoxygenation injury by activating the PI3K/AKT signaling pathway

“…The most effective intervention for acute myocardial infarction is timely revascularization (1)(2)(3). However, re-establishing blood to ischemic areas yields additional myocardial damage including inflammation, apoptosis and autophagy, which is known as myocardial ischemia/reperfusion (I/R) injury (MIRI) (1)(2)(3).…”

“…The most effective intervention for acute myocardial infarction is timely revascularization (1)(2)(3). However, re-establishing blood to ischemic areas yields additional myocardial damage including inflammation, apoptosis and autophagy, which is known as myocardial ischemia/reperfusion (I/R) injury (MIRI) (1)(2)(3). The pathophysiological mechanism of MIRI is complex and numerous studies have confirmed that endoplasmic reticulum (ER) stress (ERS)-induced apoptosis serves important roles in the progression of MIRI (4,5).…”