Flare events are mainly due to magnetic reconnection and thus are indicative of stellar activity. The Kepler Space Observatory records numerous stellar activities with unprecedented high photometric precision in flux measurements. It is perfectly suitable for carrying out a statistical study of flares. Here we present 540 M dwarfs with flare events discovered using Kepler long-cadence data. The normalized flare energy, as defined by the ratio to bolometric stellar luminosity, L L flare bol , is used to indicate the flare activity. We find that, similar to the X-ray luminosity relation, the L L flare bol versus P rot relation can also be described with three phases, supersaturation, saturation, and exponential decay, corresponding to an ultra-short period, a short period, and a long period. The flare activity and the number fraction of flaring stars in M dwarfs rise steeply near M4, which is consistent with the prediction of a turbulent dynamo. The size of starspots are positively correlated with flare activity. The L L flare bol ratio has a power-law dependence on L L H bol a , a parameter indicative of stellar chromosphere activity. According to this relation, a small enhancement in chromosphere activity may cause a huge rise in flare energy, which suggests that superflares or hyperflares may not need an extra excitation mechanism. Through a comparison study, we suggest that flare activity is a more suitable indicator for stellar activity, especially in the boundary region. However, contrary to what is expected, some M dwarfs with strong flares do not show any light variation caused by starspots. Follow-up observations are needed to investigate this problem.

Protein tyrosine phosphatase interacting protein 51 (PTPIP51) participates in multiple cellular processes, and dysfunction of PTPIP51 is implicated in diseases such as cancer and neurodegenerative disorders. However, there is no functional evidence showing the physiological or pathological roles of PTPIP51 in the heart. We have therefore investigated the role and mechanisms of PTPIP51 in regulating cardiac function. We found that PTPIP51 was markedly upregulated in ischemia/reperfusion heart. Upregulation of PTPIP51 by adenovirus-mediated overexpression markedly increased the contact of mitochondria-sarcoplasmic reticulum (SR), elevated mitochondrial Ca2+ uptake from SR release through mitochondrial Ca2+uniporter. Inhibition or knockdown of mitochondrial Ca2+uniporter reversed PTPIP51-mediated increase of mitochondrial Ca2+ and protected cardiomyocytes against PTPIP51-mediated apoptosis. More importantly, cardiac specific knockdown of PTPIP51 largely reduced myocardium infarction size and heart injury after ischemia/reperfusion. Our study defines a novel and essential function of PTPIP51 in the cardiac ischemia/reperfusion process by mediating mitochondria-SR contact. Downregulation of PTPIP51 improves heart function after ischemia/reperfusion injury, suggesting PTPIP51 as a therapeutic target for ischemic heart diseases.

Myocardial infarction is caused by insufficient coronary blood supply, which leads to myocardial damage and eventually the heart failure. Molecular mechanisms associated with the loss of cardiomyocytes during myocardial infarction (MI) and ischemia-related cardiac diseases are not yet fully understood. Nogo-C is an endoplasmic reticulum protein ubiquitously expressed in tissues including in the heart, however, the cardiac function of Nogo-C is still unknown. In the present study, we found that Nogo-C was upregulated in mouse hearts after MI, and hypoxic treatments also increased Nogo-C protein level in cardiomyocytes. Adenovirus mediated overexpression of Nogo-C led to cardiomyocyte apoptosis, whereas knockdown of Nogo-c by shRNA protected cardiomyocytes from hypoxia-induced cell apoptosis. Importantly, Nogo-C knockout mice displayed improved cardiac function, smaller infarct area, and less apoptotic cells after MI. Moreover, we found that miR-182 negatively regulated Nogo-C expression and was downregulated during MI, expressing miR-182 in cardiomyocytes protected hypoxia- and Nogo-C-mediated cell apoptosis. Our results indicate that increased cardiac Nogo-C expression is both sufficient and necessary for ischemia-induced cardiomyocyte apoptosis and cardiac dysfunction, suggesting that deregulation of Nogo-C by miRNA may be a potential therapeutic target for ischemia-related heart diseases.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of cell death is important to protect cardiac function after I/R injury. The process of reperfusion can lead to multiple types of cardiomyocyte death, including necrosis, apoptosis, autophagy, and ferroptosis. However, the time point at which the various modes of cell death occur after reperfusion injury and the mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear. METHODS: Using a left anterior descending coronary artery ligation mouse model, we sought to investigate the time point at which the various modes of cell death occur after reperfusion injury. To discover the key molecules involved in cardiomyocyte ferroptosis, we performed a metabolomics study. Loss/gain-of-function approaches were used to understand the role of 15-lipoxygenase (Alox15) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) in myocardial I/R injury. RESULTS: We found that apoptosis and necrosis occurred in the early phase of I/R injury, and that ferroptosis was the predominant form of cell death during the prolonged reperfusion. Metabolomic profiling of eicosanoids revealed that Alox15 metabolites accumulated in ferroptotic cardiomyocytes. We demonstrated that Alox15 expression was specifically increased in the injured area of the left ventricle below the suture and colocalized with cardiomyocytes. Furthermore, myocardial-specific knockout of Alox15 in mice alleviated I/R injury and restored cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic acid by Alox15, was identified as a trigger for cardiomyocyte ferroptosis. We explored the mechanism underlying its effects and found that 15-HpETE promoted the binding of Pgc1α to the ubiquitin ligase ring finger protein 34, leading to its ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis and abnormal mitochondrial morphology were observed. ML351, a specific inhibitor of Alox15, increased the protein level of Pgc1α, inhibited cardiomyocyte ferroptosis, protected the injured myocardium, and caused cardiac function recovery. CONCLUSIONS: Together, our results established that Alox15/15-HpETE–mediated cardiomyocyte ferroptosis plays an important role in prolonged I/R injury.

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