Akap1 deficiency promotes mitochondrial aberrations and exacerbates cardiac injury following permanent coronary ligation via enhanced mitophagy and apoptosis

A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1(-/-)), Siah2 knockout mice (Siah2(-/-)) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1(-/-) mice displayed larger infarct size compared to Siah2(-/-) or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1(-/-) mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1(-/-) mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets

Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents : a position paper of the ESC Working Group on Myocardial Function

This work was supported by AIRC IG grant 2016 19032 to S.Z.; FEDER through Compete 2020 –Programa Operacional Competitividade E Internacionalização(POCI), the project DOCNET (norte-01-0145-feder-000003), supported by Norte Portugal regional operational programme (norte 2020), under the Portugal 2020 partnership agreement, through the European Regional Development Fund (ERDF), the project NETDIAMOND (POCI-01-0145-FEDER-016385), supported by European Structural And Investment Funds, Lisbon’s regional operational program 2020 to I.P.F.; grants from FSR-FNRS, FRC (Cliniques Universitaires Saint-Luc) and from Action de Recherche Concertée (UCLouvain) to C.B., E.P.D. and L.B; the ERA-Net-CVD project MacroERA,01KL1706, FP7-Homage N° 305507, and IMI2-CARDIATEAM (N° 821508)to S.H.,the DZHK (German Centre for Cardiovascular Research) and the German Ministry of Research and Education (BMBF)to F.W., T.E. and L.C., the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, CVON Arena-PRIME, 2017-18, Flemish Research FoundationFWO G091018N and FWO G0B5930N to S.H.; Federico II University/Ricerca di Ateneo grant to C.G..T.; the European Research Area Networks on Cardiovascular Diseases (ERA-CVD) [LYMIT-DIS 2016, MacroERA], Fonds Wetenschappelijk Onderzoek [1160718N] to I.C; the Deutsche Forschungsgemeinschaft (DFG TH903/20-1, KFO311), the Transregio-SFB INST 95/15641 and the EU Horizon 2020 project Cardioregenix (GA 825670)to T.TPeer reviewedPostprin

The involvement of area 8B in a switching system to control eye and ear orienting processes in Macaca monkey

Aim: the purpose of this study was to investigate unit activity of area 8B, rostral to the dorsal premotor cortex, in relation to different environmental acoustic stimuli and the effect of the engagement of attention during visual fixation

MAY THE WARNING AUDITORY-VISUAL NEURONS HELP THE MONKEY TO PLAY THE PIANO?

Aim: In previous reports, we showed the involvement of PEEF (area 8B) neurons in auditory information processing and in ear and eye orienting behaviour. For what concerns auditory cells, we observed, by unit activity recording, that their activity was related to complex environmental auditory stimuli but not to pure tones. Our question was: if we train intensively a monkey, much more than previous animals, to receive the reward only after having listened to a particular note, may the monkey's neurons discriminate different notes?Methods: For this aim, we trained intensively a Macaque monkey to receive some drops of fruit juice only after having listened to a particular note (FA), while it did not receive the reward after the presentation of a different note (DO). Moreover, during the experiments also the note SOL was presented without reward. The animal was also trained for a classic visual fixation task.Results: We recorded two types of cells: a) classic auditory environmental neurons and b) neurons that discharged for FA and SOL notes but not for DO note. The discharge was brisk for the FA note, it was less intensive with a rapid adaptation for the SOL note and very weak for the DO note. In addition the discharge was scarce for the clik of the pump, and active during visual fixation task before the clik of the pump.Conclusion: Present data confirm the role of the PEEF in auditory-visual integration and expand the vision of this field. The presence of cross modal neurons (auditory-visual) and the ability to discriminate between different notes suggest to speculate that this field may be involved in music learning

Cholecystocolonic fistula in exacerbated chronic cholecystitis: A case report

The cholecystocolonic fistula (CCF) is an atypical variant of biliary disease, and it is the second most common intestinal fistula after cholecystoduodenal fistula. Intraoperative diagnosis is frequent, which implies challenging surgical management, especially in patients, often aged, with comorbidities. The rarity of this condition, atypical and various presentation, diagnostic and management complexity, makes it a unique surgical entity. We report our experience of an 84-year-old man with a history of chronic cholecystitis who presented with nonspecific symptoms. The imaging tests aroused the suspicion of gallbladder-colic fistula in the preoperative diagnosis, facilitating the subsequent surgical treatment that confirmed the diagnosis

The main determinants of diabetes mellitus vascular complications: Endothelial dysfunction and platelet hyperaggregation

Diabetes mellitus is a common disease that affects 3–5% of the general population in Italy. In some countries of northern Europe or in North America, it can even affect 6–8% of the population. Of great concern is that the number of cases of diabetes is constantly increasing, probably due to the increase in obesity and the sedentary nature of the population. According to the World Health Organization, in the year 2030 there will be 360 million people with diabetes, compared to 170 million in 2000. This has important repercussions on the lives of patients and their families, and on health systems that offer assistance to patients. In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet hyperaggregation, highlighting the main molecular mechanisms involved and the interconnections

Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure

The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF

Correction: Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0154076.]

Dermcidin: a skeletal muscle myokine modulating cardiomyocyte survival and infarct size after coronary artery ligation

Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse outcome. However, the molecular mechanisms underlying these effects are currently unknown

PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts

PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2a/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease