Melatonin Attenuates Ischemia/Reperfusion-Induced Oxidative Stress by Activating Mitochondrial Fusion in Cardiomyocytes.

Myocardial ischemia/reperfusion (I/R) injury can stimulate mitochondrial reactive oxygen species production. Optic atrophy 1- (OPA1-) induced mitochondrial fusion is an endogenous antioxidative mechanism that preserves the mitochondrial function. In our study, we investigated whether melatonin augments OPA1-dependent mitochondrial fusion and thus maintains redox balance during myocardial I/R injury. In hypoxia/reoxygenation- (H/R-) treated H9C2 cardiomyocytes, melatonin treatment upregulated OPA1 mRNA and protein expression, thereby enhancing mitochondrial fusion. Melatonin also suppressed apoptosis in H/R-treated cardiomyocytes, as evidenced by increased cell viability, diminished caspase-3 activity, and reduced Troponin T secretion; however, silencing OPA1 abolished these effects. H/R treatment augmented mitochondrial ROS production and repressed antioxidative molecule levels, while melatonin reversed these changes in an OPA1-dependent manner. Melatonin also inhibited mitochondrial permeability transition pore opening and maintained the mitochondrial membrane potential, but OPA1 silencing prevented these outcomes. These results illustrate that melatonin administration alleviates cardiomyocyte I/R injury by activating OPA1-induced mitochondrial fusion and inhibiting mitochondrial oxidative stress.

The YAP/SERCA2a signaling pathway protects cardiomyocytes against reperfusion-induced apoptosis.

Mitochondria and the endoplasmic reticulum (ER) are known to promote cardiac ischemia/reperfusion (I/R) injury. Overexpression of yes-associated protein (YAP) and/or sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) has been shown to protect cardiomyocytes against I/R-induced injury. Here, we show that activation of the YAP/SERCA2a pathway attenuated mitochondrial damage and ER stress (ERS) to maintain cardiomyocyte viability in the setting of I/R injury. Our results demonstrate that I/R treatment reduced the transcription and expression of YAP and SERCA2a, along with a decline in cardiomyocyte viability. The overexpression of YAP promoted SERCA2a transcription, whereas SERCA2a upregulation did not affect the YAP transcription, suggesting that YAP functions upstream of SERCA2a. Activation of the YAP/SERCA2a pathway suppressed mitochondrial damage by sustaining the mitochondrial redox balance and restoring mitochondrial bioenergetics. Additionally, its activation repressed ERS, reduced calcium overload, and eventually blocked caspase activation. The knockdown of SERCA2a suppressed the protective effects of YAP overexpression on mitochondrial damage and ERS. Overall, our findings reveal that the YAP/SERCA2a pathway attenuates the mitochondrial damage and ERS in response to cardiac I/R injury by regulating the mitochondria-ER communication.

MicroRNA-208-5p regulates myocardial injury of sepsis mice via targeting SOCS2-mediated NF-κB/HIF-1α pathway.

BACKGROUND: Accumulating evidence has revealed the roles of microRNAs (miRs) in sepsis, hence, the aim of the present study was to investigate whether miR-208a-5p affects sepsis whilst attempting to elucidate the mechanisms by which the suppressors of cytokine signaling 2 (SOCS2)-mediated nuclear factor-kappaB/hypoxia-inducible factor-1α (NF-κB/HIF-1α) pathway is implicated in this process. METHODS: The sepsis model was established by cecal ligation and puncture in mice. Serum levels of myocardial enzyme cardiac Troponin-I (cTnI) and brain natriuretic peptide (BNP) in mice were measured. Malondialdehyde (MDA), lactate dehydrogenase (LDH) activity, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB p65, HIF-1α and superoxidedismutase (SOD) activity in myocardial tissues were determined. Furthermore, the swelling degree of mitochondria and the apoptosis of cardiomyocytes was measured. The expression of miR-208a-5p, SOCS2, Bcl-2, Bax, NF-κB p65 and HIF-1α in myocardial tissues of mice were detected. RESULTS: Down-regulation of miR-208a-5p and up-regulation of SOCS2 raised the activity of SOD, while reduced the activity of LDH and MDA and the concentrations of cTnI, BNP, TNF-α, IL-6, NF-κB p65 and HIF-1α in mice with sepsis. Down-regulated miR-208a-5p and up-regulated SOCS2 reduced degree of mitochondria swelling, and suppressed cardiomyocytes apoptosis in mice with sepsis. MiR-208a-5p, NF-κB p65 and HIF-1α expression were raised while SOCS2 expression was depressed in myocardial tissues of mice with sepsis. CONCLUSION: This study suggests that high expression of SOCS2 or inhibition of miR-208a-5p alleviates the myocardial injury of sepsis mice via modulating NF-κB/HIF-1α pathway, which are potential candidate markers and therapeutic targets for sepsis mice.

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.

Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway.

Cardiac microvascular ischemia-reperfusion (IR) injury has been a neglected topic in recent decades. In the current study, we investigated the mechanism underlying microvascular IR injury, with a focus on mitochondrial homeostasis. We also explored the protective role of tanshinone IIA (Tan IIA) in microvascular protection in the context of IR injury. Through animal studies and cell experiments, we demonstrated that IR injury mediated microvascular wall destruction, lumen stenosis, perfusion defects, and cardiac microvascular endothelial cell (CMEC) apoptosis via inducing mitochondrial damage. In contrast, Tan IIA administration had the ability to sustain CMEC viability and microvascular homeostasis, finally attenuating microvascular IR injury. Function studies have confirmed that the SIRT1/PGC1α pathway is responsible for the microvascular protection from the Tan IIA treatment. SIRT1 activation by Tan IIA sustained the mitochondrial potential, alleviated the mitochondrial pro-apoptotic factor leakage, reduced the mPTP opening, and blocked mitochondrial apoptosis, providing a survival advantage for CMECs and preserving microvascular structure and function. By comparison, inhibiting SIRT1 abrogated the beneficial effects of Tan IIA on mitochondrial function, CMEC survival, and microvascular homeostasis. Collectively, this study indicated that Tan IIA should be considered a microvascular-protective drug that alleviates acute cardiac microcirculation IR injury via activating the SIRT1/PGC1α pathway and thereby blocking mitochondrial damage.

Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through attenuating ER stress and mitochondrial dysfunction.

Viral myocarditis has been found to be one of the leading causes of sudden death in young adults. However, no effective drugs have been developed to intervene the progression of myocarditis. Accordingly, the present study is carried out to explore the protective role played by melatonin in the setting of viral myocarditis with a focus on Mst1-Hippo pathway, mitochondrial dysfunction and ER stress. Cardiac function was determined via echocardiographic examination. Mitochondrial function and ER stress were detected via ELISA, western blots, and immunofluorescence. Our data demonstrated that virus injection induced cardiac dysfunction as evidenced by reduced contractile function in myocardium. Besides, LDH release assay and western blotting analysis demonstrated that cardiomyocyte death was activated by virus injection. Interestingly, melatonin treatment improved cardiac function and repressed virus-mediated cardiomyocyte apoptosis. At the molecular levels, mitochondrial dysfunction was induced by virus infection, as indicated by mitochondrial membrane potential reduction, mPTP opening rate elevation and caspase-9-related apoptosis activation. Besides, ER stress parameters were also elevated in virus-treated cardiomyocytes. Interestingly, melatonin treatment maintained mitochondrial dysfunction and repressed ER stress. To the end, we found that Mst1 was upregulated by virus infection; this effect was attenuated through supplementation with melatonin. However, Mst1 overexpression reduced the beneficial impact exerted by melatonin on cardiomyocyte viability, mitochondrial function and ER homeostasis. Our study illustrated that melatonin treatment attenuated viral myocarditis via sustaining cardiomyocyte viability, repressing mitochondrial dysfunction and inhibiting ER stress in a manner dependent on Mst1 inhibition.

Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway.

Irisin plays a protective effect in acute and chronic myocardial damage, but its role in septic cardiomyopathy is unclear. The aim of our study was to explore the in vivo and in vitro effects of irisin using an LPS-induced septic cardiomyopathy model. Our results demonstrated that irisin treatment attenuated LPS-mediated cardiomyocyte death and myocardial dysfunction. At the molecular level, LPS application was associated with mitochondrial oxidative injury, cardiomyocyte ATP depletion and caspase-related apoptosis activation. In contrast, the irisin treatment sustained mitochondrial function by inhibiting DRP1-related mitochondrial fission and the reactivation of mitochondrial fission impaired the protective action of irisin on inflammation-attacked mitochondria and cardiomyocytes. Additionally, we found that irisin modulated DRP1-related mitochondrial fission through the JNK-LATS2 signaling pathway. JNK activation and/or LATS2 overexpression abolished the beneficial effects of irisin on LPS-mediated mitochondrial stress and cardiomyocyte death. Altogether, our results illustrate that LPS-mediated activation of DRP1-related mitochondrial fission through the JNK-LATS2 pathway participates in the pathogenesis of septic cardiomyopathy. Irisin could be used in the future as an effective therapy for sepsis-induced myocardial depression because it corrects DRP1-related mitochondrial fission and normalizes the JNK-LATS2 signaling pathway.

[Diagnostic value of cardiac magnetic resonance in patients with acute viral myocarditis].

OBJECTIVE: To assess the diagnostic value of cardiac magnetic resonance (CMR) in patients with acute viral myocarditis. METHODS: Thirty patients with suspected acute viral myocarditis admitted in first people's hospital of Shunde from June 2011 to June 2013 were included in this prospective study. The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of acute viral myocarditis were evaluated by clinical diagnosis. Diagnostic value among different scan methods and Lake Louise criteria were compared. RESULTS: Acute viral myocarditis was diagnosed in 63.33% (19/30) patients.Values for sensitivity, specificity, PPV, NPV, and diagnostic accuracy within the overall cohort were 57.89%, 72.73%, 78.57%, 50.00%, 63.33%, respectively by edema imaging (ER).Values for sensitivity, specificity, PPV, NPV, and diagnostic accuracy within the overall cohort were 78.95%, 63.64%, 78.95%, 63.64%, 73.33%, respectively using global relative enhancement (gRE).Values for sensitivity, specificity, PPV, NPV, and diagnostic accuracy within the overall cohort were 78.95%, 54.55%, 75.00%, 60.00%, 70.00%, respectively using late gadolinium enhancement (LGE) criteria.Values for sensitivity, specificity, PPV, NPV, and diagnostic accuracy within the overall cohort were 84.21%, 81.82%, 88.89%, 75.00%, 83.33% using Lake Louise criteria. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy using Lake Louise criteria were significantly higher than using ER, gRE, LGE alone(all P < 0.05).Specificity was higher using ER than using gRE and LGE (both P < 0.05). The sensitivity, NPV, and diagnostic accuracy were significantly higher using gRE than using ER (all P < 0.05) and was similar as using LGE (all P > 0.05). CONCLUSION: Cardiac magnetic resonance is an excellent imaging modality for the diagnosis of acute viral myocarditis.