Endogenous muscle atrophy F-box is involved in the development of cardiac rupture after myocardial infarction.

Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise. The role of MAFbx in the regulation of cardiac remodeling after myocardial infarction (MI) remains unclear. Permanent coronary ligation of the left coronary artery was performed on MAFbx knockout (KO) and wild-type (WT) mice and MAFbx expression in the WT mice was shown to be significantly increased in the left ventricles after MI. The mortality rate due to post-MI cardiac rupture was significantly decreased in MAFbx KO mice compared to that in the WT mice. DNA microarray and mRNA expression analyses revealed that the upregulation of genes involved in inflammatory processes and cell motility of leukocytes and neutrophils, including Mmp9, Il1b, Cxcl2, and Nlrp3, was significantly attenuated in MAFbx KO mice 1 day after MI. MAFbx downregulation inhibited nuclear factor-κB (Nfkb) activation after MI. Flow cytometry results demonstrated that the myocardial infiltration of neutrophils was suppressed in MAFbx KO mice 1 day after MI. Nlrp3 and Il1b protein levels were decreased in MAFbx KO mice compared with those in the WT mice. MAFbx downregulation significantly attenuated Tnfa-induced Cxcl2, Il1b, and Nlrp3 expression in cardiomyocytes. We conclude that MAFbx plays an important role in the mediation of excessive inflammation, including neutrophil infiltration, inflammasome formation, and production of proinflammatory cytokines through the activation of Nfkb, promoting cardiac rupture after MI.

ß-Cryptoxanthin exerts greater cardioprotective effects on cardiac ischemia-reperfusion injury than astaxanthin by attenuating mitochondrial dysfunction in mice.

SCOPE: ß-Cryptoxanthin and astaxanthin are antioxidant carotenoid pigments that inhibit lipid peroxidation as potently as vitamin E. We hypothesized that acute treatment with ß-cryptoxanthin and astaxanthin causes similar reductions in the sizes of cardiac infarcts caused by ischemia-reperfusion (I/R) injury by attenuating oxidative stress and cardiac mitochondrial dysfunction. METHODS AND RESULTS: C57BL/6 mice (n = 36) were randomized to receive vehicle, ß-cryptoxanthin, astaxanthin, or vitamin E at 50 mg/kg by gavage feeding prior to I/R injury. Cardiac I/R was induced by left anterior descending coronary artery ligation followed by reperfusion. All treatments significantly reduced infarct sizes by 36-57%, attenuated apoptosis and also attenuated cardiac mitochondrial dysfunction in the treated groups compared to the control group. Although astaxanthin and vitamin E exhibited similar efficacy with respect to cardioprotection, ß-cryptoxanthin exhibited greater efficacy than its counterparts, as it reduced infarct sizes by 60%. ß-Cryptoxanthin was more effective than astaxanthin and vitamin E because it reduced cardiac mitochondrial swelling, mitochondrial depolarization, the Bax/Bcl-2 ratio, and plasma and cardiac thiobarbituric acid reactive substances levels more significantly than its counterparts. CONCLUSION: Acute ß-cryptoxanthin treatment exhibits greater cardioprotective efficacy against I/R injury than astaxanthin and vitamin E by reducing infarct sizes and attenuating apoptosis, oxidative stress, and mitochondrial dysfunction.

Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response.

BACKGROUND: The unfolded protein response (UPR) plays a pivotal role in ischemia-reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice. METHODS: Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA. RESULTS: At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2α-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1α1, brain natriuretic peptide, and α skeletal muscle actin in LV at 21 days after I/R. CONCLUSION: Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.