FTO in health and disease.

Fat mass and obesity-associated (FTO) protein, a key enzyme integral to the dynamic regulation of epitranscriptomic modifications in RNAs, significantly influences crucial RNA lifecycle processes, including splicing, export, decay, and translation. The role of FTO in altering the epitranscriptome manifests across a spectrum of physiological and pathological conditions. This review aims to consolidate current understanding regarding the implications of FTO in health and disease, with a special emphasis on its involvement in obesity and non-communicable diseases associated with obesity, such as diabetes, cardiovascular disease, and cancer.

Unveiling the proteome of the fasting heart: Insights into HIF-1 pathway regulation.

Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis of the fasting heart and attempted to clarify the molecular basis of fasting-induced cardioprotection.

Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome.

Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet.

Glycopolymer Inhibitors of Galectin-3 Suppress the Markers of Tissue Remodeling in Pulmonary Hypertension.

Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding β-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension.

Epitranscriptomic regulation in fasting hearts: implications for cardiac health.

Cardiac tolerance to ischaemia can be increased by dietary interventions such as fasting, which is associated with significant changes in myocardial gene expression. Among the possible mechanisms of how gene expression may be altered are epigenetic modifications of RNA - epitranscriptomics. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are two of the most prevalent modifications in mRNA.

The role of mA and mAm RNA modifications in the pathogenesis of diabetes mellitus.

The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers.

RNA modification mAm: the role in cardiac biology.

Epitranscriptomic modifications have recently emerged into the spotlight of researchers due to their vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N,2'-O-dimethyladenosine (mAm) is one of the most prevalent chemical marks on RNA and is dynamically regulated by writers (PCIF1, METTL4) and erasers (FTO). The presence or absence of mAm in RNA affects mRNA stability, regulates transcription, and modulates pre-mRNA splicing.

Developmental Aspects of Cardiac Adaptation to Increased Workload.

The heart is capable of extensive adaptive growth in response to the demands of the body. When the heart is confronted with an increased workload over a prolonged period, it tends to cope with the situation by increasing its muscle mass. The adaptive growth response of the cardiac muscle changes significantly during phylogenetic and ontogenetic development.

and investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline.

Although proteasome inhibitors (PIs) are modern targeted anticancer drugs, they have been associated with a certain risk of cardiotoxicity and heart failure (HF). Recently, PIs have been combined with anthracyclines (ANTs) to further boost their anticancer efficacy. However, this raised concerns regarding cardiac safety, which were further supported by several studies on immature cardiomyocytes.

Selection of optimal reference genes for gene expression studies in chronically hypoxic rat heart.

Adaptation to chronic hypoxia renders the heart more tolerant to ischemia/reperfusion injury. To evaluate changes in gene expression after adaptation to chronic hypoxia by RT-qPCR, it is essential to select suitable reference genes. In a chronically hypoxic rat model, no specific reference genes have been identified in the myocardium.

Interaction between the integrin Mac-1 and signal regulatory protein α (SIRPα) mediates fusion in heterologous cells.

Macrophage fusion leading to the formation of multinucleated giant cells is a hallmark of chronic inflammation. Several membrane proteins have been implicated in mediating cell-cell attachment during fusion, but their binding partners remain unknown. Recently, we demonstrated that interleukin-4 (IL-4)-induced fusion of mouse macrophages depends on the integrin macrophage antigen 1 (Mac-1).

Anti-arrhythmic Cardiac Phenotype Elicited by Chronic Intermittent Hypoxia Is Associated With Alterations in Connexin-43 Expression, Phosphorylation, and Distribution.

Remodeling of the cellular distribution of gap junctions formed mainly by connexin-43 (Cx43) can be related to the increased incidence of cardiac arrhythmias. It has been shown that adaptation to chronic intermittent hypobaric hypoxia (IHH) attenuates the incidence and severity of ischemic and reperfusion ventricular arrhythmias and increases the proportion of anti-arrhythmic n-3 polyunsaturated fatty acids (n-3 PUFA) in heart phospholipids. Wistar rats were exposed to simulated IHH (7,000 m, 8-h/day, 35 exposures) and compared with normoxic controls (N).

Do different nuclei in a binucleated cardiomyocyte have different rates of nuclear protein import?

The functional significance of having two nuclei in a cell is unknown. Having two stores of genetic material may be advantageous for cell growth. Nuclear protein import is at a critical juncture in the cell to modify cell growth.

Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3.

Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1α in such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion.

Heat shock protein 60 involvement in vascular smooth muscle cell proliferation.

Aim: Heat shock protein 60 (Hsp60) is a mediator of stress-induced vascular smooth muscle cell (VSMC) proliferation. This study will determine, first, if the mitochondrial or cytoplasmic localization of Hsp60 is critical to VSMC proliferation and, second, the mechanism of Hsp60 induction of VSMC proliferation with a focus on modification of nucleocytoplasmic trafficking.

Methods And Results: Hsp60 was overexpressed in primary rabbit VSMCs with or without a mitochondrial targeting sequence (AdHsp60).

Proteomic analysis of cardiac ventricles: baso-apical differences.

The heart is characterized by a remarkable degree of heterogeneity. Since different cardiac pathologies affect different cardiac regions, it is important to understand molecular mechanisms by which these parts respond to pathological stimuli. In addition to already described left ventricular (LV)/right ventricular (RV) and transmural differences, possible baso-apical heterogeneity has to be taken into consideration.

Antioxidant tempol suppresses heart cytosolic phospholipase Aα stimulated by chronic intermittent hypoxia.

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia-reperfusion injury. Phospholipases A (PLAs) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA (cPLAα), its phosphorylated form (p-cPLAα), calcium-independent (iPLA), and secretory (sPLAIIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats.

Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats.

Mitochondria play an essential role in improved cardiac ischaemic tolerance conferred by adaptation to chronic hypoxia. In the present study, we analysed the effects of continuous normobaric hypoxia (CNH) on mitochondrial functions, including the sensitivity of the mitochondrial permeability transition pore (MPTP) to opening, and infarct size (IS) in hearts of spontaneously hypertensive rats (SHR) and the conplastic SHR-mt strain, characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischaemia-resistant brown Norway (BN) strain. Rats were adapted to CNH (10% O, 3 weeks) or kept at room air as normoxic controls.

Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia.

Chronic hypoxia and exercise are natural stimuli that confer sustainable cardioprotection against ischemia-reperfusion (I/R) injury, but it is unknown whether they can act in synergy to enhance ischemic resistance. Inflammatory response mediated by tumor necrosis factor-α (TNF-α) plays a role in the infarct size limitation by continuous normobaric hypoxia (CNH), whereas exercise is associated with anti-inflammatory effects. This study was conducted to determine if exercise training performed under conditions of CNH (12% O) affects myocardial ischemic resistance with respect to inflammatory and redox status.

Chronic intermittent hypoxia affects the cytosolic phospholipase Aα/cyclooxygenase 2 pathway via β-adrenoceptor-mediated ERK/p38 stimulation.

Cardiac resistance against acute ischemia/reperfusion (I/R) injury can be enhanced by adaptation to chronic intermittent hypoxia (CIH), but the changes at the molecular level associated with this adaptation are still not fully explored. Phospholipase A (PLA) plays an important role in phospholipid metabolism and may contribute to membrane destruction under conditions of energy deprivation during I/R. The aim of this study was to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLAα (cPLAα) and its phosphorylated form (p-cPLAα), as well as other related signaling proteins in the left ventricular myocardium of adult male Wistar rats.

A rapid HPLC column switching method for sample preparation and determination of β-carotene in food supplements.

A simple and automated HPLC column-switching method with rapid sample pretreatment has been developed for quantitative determination of β-carotene in food supplements. Commercially samples of food supplements were dissolved in chloroform with help of saponification with 1M solution of sodium hydroxide in ultrasound bath. A 20-min sample dissolution/extraction step was necessary before chromatography analysis to transfer β-carotene from solid state of food supplements preparations (capsules,tablets) to chloroform solution.

Pharmacological activation of mitochondrial BK(Ca) channels protects isolated cardiomyocytes against simulated reperfusion-induced injury.

The aim of this study was to find out whether opening of mitochondrial large-conductance Ca(2+)-activated potassium channels (BK(Ca)) protects cardiomyocytes against injury caused by simulated ischemia and reperfusion. This study also aimed to determine whether the protective mechanism involves signaling by reactive oxygen species (ROS) and phosphatidylinositol-3-kinase (PI3K). We used isolated ventricular myocytes, which are believed to contain no functional BK(Ca) channels in the sarcolemma.

Up-regulation and redistribution of protein kinase C-δ in chronically hypoxic heart.

The adaptation to chronic hypoxia confers long-lasting cardiac protection against acute ischemia-reperfusion injury. Protein kinase C (PKC) appears to play a role in the cardioprotective mechanism but the involvement of individual PKC isoforms remains unclear. The aim of this study was to examine the effects of chronic intermittent hypoxia (CIH; 7,000 m, 8 h/day) and acute administration of PKC-δ inhibitor (rottlerin, 0.

Dietary polyunsaturated fatty acids and adaptation to chronic hypoxia alter acyl composition of serum and heart lipids.

The effects of dietary supplementation with fat of different fatty acid profile and chronic intermittent hypoxia (CIH) on the fatty acid composition of serum and heart lipids were analysed. Adult male Wistar rats were fed a standard non-fat diet enriched with 10 % of lard, fish oil (n-3 PUFA) or maize oil (n-6 PUFA) for 10 weeks. After 4 weeks on the diets, each group was divided in two subgroups, either exposed to CIH in a barochamber (7000 m, twenty-five exposures) or kept at normoxia.