AMPKα2 Overexpression Reduces Cardiomyocyte Ischemia-Reperfusion Injury Through Normalization of Mitochondrial Dynamics.

Cardiac ischemia-reperfusion (I/R) injury is associated with mitochondrial dysfunction. Recent studies have reported that mitochondrial function is determined by mitochondrial dynamics. Here, we hypothesized that AMPKα2 functions as an upstream mediator that sustains mitochondrial dynamics in cardiac I/R injury and cardiomyocyte hypoxia-reoxygenation (H/R) in vitro. To test this, we analyzed cardiomyocyte viability and survival along with mitochondrial dynamics and function using western blots, qPCR, immunofluorescence, and ELISA. Our results indicated that both AMPKα2 transcription and translation were reduced by H/R injury in cardiomyocytes. Decreased AMPKα2 levels were associated with cardiomyocyte dysfunction and apoptosis. Adenovirus-mediated AMPKα2 overexpression dramatically inhibited H/R-mediated cardiomyocyte damage, possibly by increasing mitochondrial membrane potential, inhibiting cardiomyocyte oxidative stress, attenuating intracellular calcium overload, and inhibiting mitochondrial apoptosis. At the molecular level, AMPKα2 overexpression alleviated abnormal mitochondrial division and improved mitochondrial fusion through activation of the Sirt3/PGC1α pathway. This suggests AMPKα2 contributes to maintaining normal mitochondrial dynamics. Indeed, induction of mitochondrial dynamics disorder abolished the cardioprotective effects afforded by AMPKα2 overexpression. Thus, cardiac I/R-related mitochondrial dynamics disorder can be reversed by AMPKα2 overexpression in a manner dependent on the activation of Sirt3/PGC1α signaling.

Combination of melatonin and irisin ameliorates lipopolysaccharide-induced cardiac dysfunction through suppressing the Mst1-JNK pathways.

Despite significant advances in therapies in past decades, the mortality rate of septic cardiomyopathy remains high. The aim of this study is to explore the therapeutic effects of combined treatment using melatonin and irisin in a mouse model of lipopolysaccharide (LPS)-mediated septic cardiomyopathy. Our data found that melatonin and irisin could further attenuate LPS-induced myocardial depression. Molecular investigation illustrated that melatonin and irisin cotreatment sustained cardiomyocyte viability and improved mitochondrial function under LPS stress. Pathway analysis demonstrated that macrophage-stimulating 1 (Mst1), which was significantly activated by LPS, was drastically inhibited by melatonin/irisin cotreatment. Mechanically, Mst1 activated c-Jun N-terminal kinase (JNK) pathway and the latter induced oxidative stress, adenosine triphosphate metabolism disorder, mitochondrial membrane potential reduction, and cardiomyocyte death activation. Melatonin and irisin cotreatment effectively inhibited the Mst1-JNK pathway and, thus, promoted cardiomyocyte survival and mitochondrial homeostasis. Interestingly, Mst1 overexpression abolished the beneficial effects of melatonin and irisin in vivo and in vitro. Altogether, our results confirmed that melatonin and irisin combination treatment could protect heart against sepsis-induced myocardial depression via modulating the Mst1-JNK pathways.

Drag-reducing polymers increase exercise tolerance in an ischemic hind-limb rat model.

OBJECTIVE: Drag-reducing polymers are long-chain, blood soluble macromolecules that can improve microcirculation in vivo. This study aimed to examine the effects of drag-reducing polymers on exercise tolerance in a rat model of hind-limb ischemia. METHODS: After adaptive running training, bilateral femoral artery ligation models were established in 64 Wistar rats. During an exhaustive exercise, polyethylene oxide or normal saline was intravenously injected to each group (n = 32) at 4 mL/h for 10 min. The exhaustive exercise time was recorded, and lactic acid levels in gastrocnemius muscle and serum were measured. Serum levels of nitric oxide, creatine kinase and lactate dehydrogenase were measured as biomarkers of physical fatigue. RESULTS: Compared with saline-treated control group, rats in polyethylene oxide-treated group had longer exhaustive exercise time (774.7 ± 171.5 s vs. 687.6 ± 166.1 s, p = 0.043), and lower lactic acid level in gastrocnemius muscle (p < 0.01) but no significant difference in serum lactic acid level between two groups was observed (p > 0.05). Nitric oxide level was higher in polyethylene oxide group than in controls (p < 0.05), but no significant differences in serum creatine kinase and lactate dehydrogenase levels between two groups were observed (p > 0.05). CONCLUSION: Drag-reducing polymers contribute to the enhancement of exercise endurance and exert anti-fatigue effect.