Myocardial Connexin-43 is Implicated in the Prevention of Malignant Arrhythmia in Rats Suffering from Essential Hypertension

Gap-junction connexin (Cx) channels are important determinants of myocardial conduction and synchronization that is crucial for heart function. Hypertension-induced structural remodeling is associated with an increased risk of life-threatening arrhythmias and heart failure in both humans and experimental animals. Recent studies suggest that abnormal distribution and/or downregulation of Cx43 accompanied with altered protein kinase C (PKC)ε signaling in spontaneously hypertensive rats were linked with increased propensity to ventricular fibrillation compared to normotensive rats. By contrast, the long-term treatment of hypertensive rats with cardioprotective compounds such as melatonin, omega-3 fatty acids, or red palm oil resulted in protection from lethal arrhythmia. Their antiarrhythmic effect was attributed to the attenuation of abnormal Cx43 topology and modulation of Cx43 mRNA as well as protein expression and its functional phosphorylated forms. The latter might be attributed to upregulation of PKCε. It appears that maladaptive consequences of hypertension resulting in abnormal myocardial distribution of Cx43 and its downregulation can contribute to arrhythmogenesis and occurrence of malignant arrhythmias. On the other hand, the attenuation of myocardial Cx43 abnormalities by treatment with melatonin, omega-3 fatty acids, or red palm oil confers arrhythmia protection in rodent model of essential hypertension. Findings uncover novel mechanisms of cardioprotective effects of melatonin, omega-3 fatty acids, and red palm oil. Well-designed clinical trials are needed to explore antiarrhythmic potential of these compounds in human essential hypertension

Complex Interplay Between MAZR and Runx3 Regulates the Generation of Cytotoxic T Lymphocyte and Memory T Cells

The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8(+) T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs in vitro. However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made in vitro, the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8 alpha, Granzyme B and perforin in vivo. Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools

Irradiation-Induced Cardiac Connexin-43 and miR-21 Responses Are Hampered by Treatment with Atorvastatin and Aspirin

Radiation of the chest during cancer therapy is deleterious to the heart, mostly due to oxidative stress and inflammation related injury. A single sub-lethal dose of irradiation has been shown to result in compensatory up-regulation of the myocardial connexin-43 (Cx43), activation of the protein kinase C (PKC) signaling along with the decline of microRNA (miR)-1 and an increase of miR-21 levels in the left ventricle (LV). We investigated whether drugs with antioxidant, anti-inflammatory or vasodilating properties, such as aspirin, atorvastatin, and sildenafil, may affect myocardial response in the LV and right ventricle (RV) following chest irradiation. Adult, male Wistar rats were subjected to a single sub-lethal dose of chest radiation at 25 Gy and treated with aspirin (3 mg/day), atorvastatin (0.25 mg/day), and sildenafil (0.3 mg/day) for six weeks. Cx43, PKCε and PKCδ proteins expression and levels of miR-1 as well as miR-21 were determined in the LV and RV. Results showed that the suppression of miR-1 was associated with an increase of total and phosphorylated forms of Cx43 as well as PKCε expression in the LV while having no effect in the RV post-irradiation as compared to the non-irradiated rats. Treatment with aspirin and atorvastatin prevented an increase in the expression of Cx43 and PKCε without change in the miR-1 levels. Furthermore, treatment with aspirin, atorvastatin, and sildenafil completely prevented an increase of miR-21 in the LV while having partial effect in the RV post irradiation. The increase in pro-apoptotic PKCδ was not affected by any of the used treatment. In conclusion, irradiation and drug-induced changes were less pronounced in the RV as compared to the LV. Treatment with aspirin and atorvastatin interfered with irradiation-induced compensatory changes in myocardial Cx43 protein and miR-21 by preventing their elevation, possibly via amelioration of oxidative stress and inflammation

Omacor Protects Normotensive and Hypertensive Rats Exposed to Continuous Light from Increased Risk to Malignant Cardiac Arrhythmias

Light pollution disturbs circadian rhythm, and this can also be deleterious to the heart by increased susceptibility to arrhythmias. Herein, we investigated if rats exposed to continuous light had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. Male and female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. Half the rats were then treated with 200 mg/100 g b.w. Omacor®. Continuous light resulted in higher male rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca2+ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. This indicates that rat exposure to continuous light results in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk

Irradiation-Induced Cardiac Connexin-43 and miR-21 Responses Are Hampered by Treatment with Atorvastatin and Aspirin

Radiation of the chest during cancer therapy is deleterious to the heart, mostly due to oxidative stress and inflammation related injury. A single sub-lethal dose of irradiation has been shown to result in compensatory up-regulation of the myocardial connexin-43 (Cx43), activation of the protein kinase C (PKC) signaling along with the decline of microRNA (miR)-1 and an increase of miR-21 levels in the left ventricle (LV). We investigated whether drugs with antioxidant, anti-inflammatory or vasodilating properties, such as aspirin, atorvastatin, and sildenafil, may affect myocardial response in the LV and right ventricle (RV) following chest irradiation. Adult, male Wistar rats were subjected to a single sub-lethal dose of chest radiation at 25 Gy and treated with aspirin (3 mg/day), atorvastatin (0.25 mg/day), and sildenafil (0.3 mg/day) for six weeks. Cx43, PKCε and PKCδ proteins expression and levels of miR-1 as well as miR-21 were determined in the LV and RV. Results showed that the suppression of miR-1 was associated with an increase of total and phosphorylated forms of Cx43 as well as PKCε expression in the LV while having no effect in the RV post-irradiation as compared to the non-irradiated rats. Treatment with aspirin and atorvastatin prevented an increase in the expression of Cx43 and PKCε without change in the miR-1 levels. Furthermore, treatment with aspirin, atorvastatin, and sildenafil completely prevented an increase of miR-21 in the LV while having partial effect in the RV post irradiation. The increase in pro-apoptotic PKCδ was not affected by any of the used treatment. In conclusion, irradiation and drug-induced changes were less pronounced in the RV as compared to the LV. Treatment with aspirin and atorvastatin interfered with irradiation-induced compensatory changes in myocardial Cx43 protein and miR-21 by preventing their elevation, possibly via amelioration of oxidative stress and inflammation

CRCA_2_3_Autumn2015.indb

bACKgRoUND: It has been previously reported that various acute interventions causing myocardial abnormalities in Ca 2+ handling and defects in intercellular coupling facilitate the occurrence of malignant arrhythmias. objECTIVES: To comprehensively determine the impact of such Ca 2+ -related disorders induced in intact animal hearts on the ultrastructure of the cardiomyocytes before occurrence and during sustaining of severe arrhythmias. METhoDS: Three types of acute experiments known to be accompanied by disturbances in Ca 2+ handling were performed. Langendorff-perfused rat and guinea pig hearts were subjected to K + -deficient perfusion to induce ventricular fibrillation; Langendorff-perfused guinea pig heart underwent burst atrial pacing to induce atrial fibrillation; and open chest pig heart was used for intramyocardial noradrenaline infusion to induce ventricular tachycardia. Tissue samples for electron microscopy examination were obtained during basal conditions, previous occurrence and during sustaining of malignant arrhythmias. RESUlTS: The comparative findings suggest that myocardial heterogeneity of high [Ca 2+ ]i-induced subcellular injury of the cardiomyocytes and their junctions is a common feature that precede occurrence ventricular tachycardia, ventricular fibrillation or atrial fibrillation regardless of the species and atria/ventricular-related differences in Ca 2+ handling and intercellular coupling. The primary changes consisted of nonuniform sarcomere shortening, which most likely reflects cytosolic Ca 2+ oscillations; disturbances in Ca 2+ wave propagation; and Ca 2+ overload. These disturbances were linked with defects in cardiac cell-to-cell coupling that increased the propensity of the heart to malignant arrhythmias. Moreover, Ca 2+ overload led to disruption of myofilaments, jeopardizing contractile function. CoNClUSIoNS: The results provide a novel paradigm linking Ca 2+ -related arrhythmogenesis and contractility disorders that may contribute to acute heart failure

Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis.

The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis

Potencial markers and metabolic processes involved in mechanism of radiation-induced heart injury

Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra and intercellular signaling to alter cell and tissue function. In the case of chest irradiation it can affect the heart, blood vessels and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction and ultimate failing of the heart occur as a pathological entity - "radiation-induced heart disease" (RIHD) that is major source of morbidity and mortality. The purpose of the review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author