Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.

Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K + channel encoded by the human ether-a-gogo-related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K + channel (I Kr IntroductionThe amplitude of ion channel currents is determined by a combination of channel gating (open versus closed times) and channel density in the plasma membrane. Whereas ion channel gating is known to be modulated by various means, such as hormones and drugs, much less is known about how the density of WT ion channels in the plasma membrane is regulated.The human ether-a-go-go-related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier K + channel (I Kr ) in the heart (1, 2). Mutations in HERG reduce I Kr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias (3). In addition, the HERG channel is a common target for diverse classes of drugs that induce acquired long QT syndrome (LQTS; ref. 4). Whereas drugs usually reduce HERG channel current (I HERG ) by blocking the channel, LQTS-causing HERG mutations often decrease I HERG by disrupting forward trafficking of the channel, thereby reducing expression levels of HERG at the plasma membrane (5). However, little is presently known about how the plasma membrane density of WT HERG channels is regulated under either physiological or pathophysiological conditions. Disorders of extracellular K + concentration ([K + ] o ) are the most common electrolyte abnormality found in clinical practice and can be life threatening. For example, abrupt, insulin-induced shifts of K + from the extracellular compartment into cells, abnormal K + losses caused by digestive or kidney disorders, and the use of certain diuretics are common causes of low [K + ] o (hypokalemia). It is also

The human ether-a-go-go-related gene (hERG) encodes a channel that conducts the rapidly activating delayed rectifier K ϩ current (I Kr ), which is important for cardiac repolarization. Mutations in hERG reduce I Kr and cause congenital long QT syndrome (LQTS). More frequently, common medications can reduce I Kr and cause LQTS as a side effect. Protein trafficking abnormalities are responsible for most hERG mutation-related LQTS and are recently recognized as a mechanism for druginduced LQTS. Whereas hERG trafficking has been studied in recombinant expression systems, there has been no reported study on cardiac I Kr trafficking at the protein level. In the present study, we identified that I Kr is present in cultured neonatal rat ventricular myocytes and can be robustly recorded using Cs ϩ as the charge carrier. We further discovered that 4,4Ј-(isopropylidenedithio)-bis-(2,6-di-t-butylphenol) (probucol), a cholesterol-lowering drug that induces LQTS, disrupted I Kr trafficking and prolonged the cardiac action potential duration. Probucol did not directly block I Kr . Probucol also disrupted hERG trafficking and did not block hERG channels expressed in human embryonic kidney 293 cells. We conclude that probucol induces LQTS by disrupting ether-a-go-go-related gene trafficking, and that primary culture of neonatal rat cardiomyocytes represents a useful system for studying native I Kr trafficking.

BackgroundThe definition of hypervirulent Klebsiella pneumoniae (hvKp), traditionally regarded as hypermucoviscosity, is controversial. However, data based on both phenotype (hypermucoviscous) and genetic (aerobactin) criteria are limited.MethodsA retrospective study was conducted in 175 geriatric patients between January 2008 and January 2014. The clinical and molecular data, including antimicrobial susceptibility testing, extended-spectrum-β-lactamase (ESBL) production, virulence gene, and multilocus sequence typing of the hvKp-group (hypermucoviscosity and aerobactin positive) were compared with those of classic K. pneumoniae (cKp) isolates.ResultsOf 175 Kp isolates, 45.7% were hvKp. In pathogenicity, K1, K2, magA, rmpA, and rmpA2 genes were strongly associated with hvKp (P < 0.01). In the hvKp group, invasive infections (P < 0.000), liver abscess (P = 0.008), abdominal infection (P = 0.002) and septic shock (P = 0.035) are significantly higher than cKp group. Patients with better nutritional status were frequently infected with hvKp. However, host inflammatory reaction is most severe in hvKp group. Patients with diabetes (odds ratio [OR] = 2.548) and digestive diseases (OR = 2.196) are more likely to be infected with hvKp. Importantly, the detection of hvKp isolates increased from January 2008 to January 2010, January 2010 to January 2012, and January 2010 to January 2014 (12, 30, and 48 isolates, respectively). Overall, 16.3% of hvKp isolates produced ESBLs and 20.0% were MDR-hvKp. Multivariate analysis implied that infection occurred in the ICU (OR = 5.826) and patients with indwelling stomach tubes (OR = 6.461) are independent risk factors for ESBL-hvKp infection.ConclusionsHvKp, especially ESBL-hvKp and MDR-hvKp, is emerging in the elderly. It is essential to enhance clinical awareness and management of hvKp infections.Electronic supplementary materialThe online version of this article (10.1186/s12941-018-0302-9) contains supplementary material, which is available to authorized users.