Genome wide association meta-analyses (GWAMA) by the CORtisol NETwork (CORNET) consortium identif... more Genome wide association meta-analyses (GWAMA) by the CORtisol NETwork (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid binding globulin (CBG) in liver. These and other findings indicate that higher plasma cortisol levels are causally associated with cardiovascular disease, however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol linked Single Nucleotide Polymorphisms (SNPs) that are trans-associated with genes from 7 different vascular and metabolic tissues, finding the highest representation of trans-genes in liver, subcutaneous adipose and visceral abdominal adipose tissue (FDR = 15%). We identified a sub-set of cortisol-assoc...
In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduce... more In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduced and different intracellular protective mechanisms and their effects have been described. To study whether similar protective phenotype can be induced by hyperoxia also in humans, gene expression profile after hyperoxic exposure was analyzed. Adult patients were randomized to be ventilated with either FiO2 0.4 (n = 14) or 1.0 (n = 10) for 60 minutes before coronary artery bypass grafting. A tissue sample from the right atrial appendage was taken for gene analysis and expression profile analysis on genome wide level by RNA-seq analysis was applied. Exposure to > 96% oxygen for 60 minutes significantly changed the expression of 20 different genes, including upregulation of two different humanins - MTRNR2L2 and MTRNR2L8, and activated a "cell survival" network as detected by Ingenuity Pathway Analyses. We concluded that administration of > 96% oxygen for 1 hour changes gene expression in the myocardium of the patients with coronary artery disease and may enhance cell survival capability.
To establish a simple, reproducible model of neointima formation in mice with atherosclerotic ves... more To establish a simple, reproducible model of neointima formation in mice with atherosclerotic vessels. Apolipoprotein E/low density lipoprotein receptor double knockout mice were fed an atherogenic diet. Carotid artery injury was induced by separate ligation of the external and internal carotid artery immediately distal to the bifurcation. Mice with normal vessels were used for comparison. Monocytes and macrophages were detected with immunohistochemistry using CD68 antibodies. The transcription factor nuclear factor kappa B was also detected by immunohistochemistry. Expression of tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b) was evaluated by real time polymerase chain reaction. Neointima and media areas were digitally measured and analyzed. Four weeks later carotid artery ligation had induced neointima formation proximal to the ligation site, apparent as a smooth muscle cell alpha-actin positive layer intimal to the lamina elastica interna. The shape and size of the les...
We have established a model of adaptation to ischemia by breathing a hyperoxic gas mixture, which... more We have established a model of adaptation to ischemia by breathing a hyperoxic gas mixture, which may be directly employed in clinical practice. Hyperoxia improves postischemic function and reduces myocardial necrosis in globally and regionally ischemic rat and mouse hearts, protects hearts of animals with severe atherosclerosis, and modulates in vitro reactivity of isolated aortic rings. Hyperoxic preconditioning is most efficient when the inspired oxygen fraction is >80% oxygen, with different exposure times in rats and mice. In rats the protection is both immediate and delayed, while in mice only immediate protection can be evoked. Exposure to hyperoxia causes an oxidative stress evident as increased serum lipid peroxidation products and reduced antioxidant defence. When breathing hyperoxic gas a rapid nuclear translocation of nuclear factor kappa B (NFκB) in the lungs is followed by a cardiac NFκB activation. In conjunction with hyperoxia the mitogen activated protein kinases (MAPK) p38, ERK1/2, and JNK are phosphorylated in the heart. Pharmacological inhibition of NFκB activation abolished the beneficial effects of hyperoxia. During Langendorff-perfusion with induced global ischemia, phosphorylation of MAPK as well as translocation of NFκB is reduced in animals subjected to hyperoxia prior to the experiments, the latter perhaps due to increased formation of the NFκB inhibitor IkBα. A posssible role for the NFκB-regulated gene inducible nitric oxide synthase (iNOS) in the hyperoxia response was investigated in knock out mice, who had no functional or antiinfarct protection of preconditioning by either hyperoxia or classic ischemic preconditioning. However, neither cardiac iNOS nor contents of antioxidants, heat shock protein 70, or endothelial NOS in the heart increased after hyperoxia. Thus, the signal transduction pathways and organ effectors of hyperoxic protection are not fully determined, but appear to involve MAPK and NFκB. Hyperoxia may have a large potential in the pretreatment of patients undergoing not only open heart procedures, but also in front of any major surgery.
Genome wide association meta-analyses (GWAMA) by the CORtisol NETwork (CORNET) consortium identif... more Genome wide association meta-analyses (GWAMA) by the CORtisol NETwork (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid binding globulin (CBG) in liver. These and other findings indicate that higher plasma cortisol levels are causally associated with cardiovascular disease, however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol linked Single Nucleotide Polymorphisms (SNPs) that are trans-associated with genes from 7 different vascular and metabolic tissues, finding the highest representation of trans-genes in liver, subcutaneous adipose and visceral abdominal adipose tissue (FDR = 15%). We identified a sub-set of cortisol-assoc...
In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduce... more In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduced and different intracellular protective mechanisms and their effects have been described. To study whether similar protective phenotype can be induced by hyperoxia also in humans, gene expression profile after hyperoxic exposure was analyzed. Adult patients were randomized to be ventilated with either FiO2 0.4 (n = 14) or 1.0 (n = 10) for 60 minutes before coronary artery bypass grafting. A tissue sample from the right atrial appendage was taken for gene analysis and expression profile analysis on genome wide level by RNA-seq analysis was applied. Exposure to > 96% oxygen for 60 minutes significantly changed the expression of 20 different genes, including upregulation of two different humanins - MTRNR2L2 and MTRNR2L8, and activated a "cell survival" network as detected by Ingenuity Pathway Analyses. We concluded that administration of > 96% oxygen for 1 hour changes gene expression in the myocardium of the patients with coronary artery disease and may enhance cell survival capability.
To establish a simple, reproducible model of neointima formation in mice with atherosclerotic ves... more To establish a simple, reproducible model of neointima formation in mice with atherosclerotic vessels. Apolipoprotein E/low density lipoprotein receptor double knockout mice were fed an atherogenic diet. Carotid artery injury was induced by separate ligation of the external and internal carotid artery immediately distal to the bifurcation. Mice with normal vessels were used for comparison. Monocytes and macrophages were detected with immunohistochemistry using CD68 antibodies. The transcription factor nuclear factor kappa B was also detected by immunohistochemistry. Expression of tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b) was evaluated by real time polymerase chain reaction. Neointima and media areas were digitally measured and analyzed. Four weeks later carotid artery ligation had induced neointima formation proximal to the ligation site, apparent as a smooth muscle cell alpha-actin positive layer intimal to the lamina elastica interna. The shape and size of the les...
We have established a model of adaptation to ischemia by breathing a hyperoxic gas mixture, which... more We have established a model of adaptation to ischemia by breathing a hyperoxic gas mixture, which may be directly employed in clinical practice. Hyperoxia improves postischemic function and reduces myocardial necrosis in globally and regionally ischemic rat and mouse hearts, protects hearts of animals with severe atherosclerosis, and modulates in vitro reactivity of isolated aortic rings. Hyperoxic preconditioning is most efficient when the inspired oxygen fraction is >80% oxygen, with different exposure times in rats and mice. In rats the protection is both immediate and delayed, while in mice only immediate protection can be evoked. Exposure to hyperoxia causes an oxidative stress evident as increased serum lipid peroxidation products and reduced antioxidant defence. When breathing hyperoxic gas a rapid nuclear translocation of nuclear factor kappa B (NFκB) in the lungs is followed by a cardiac NFκB activation. In conjunction with hyperoxia the mitogen activated protein kinases (MAPK) p38, ERK1/2, and JNK are phosphorylated in the heart. Pharmacological inhibition of NFκB activation abolished the beneficial effects of hyperoxia. During Langendorff-perfusion with induced global ischemia, phosphorylation of MAPK as well as translocation of NFκB is reduced in animals subjected to hyperoxia prior to the experiments, the latter perhaps due to increased formation of the NFκB inhibitor IkBα. A posssible role for the NFκB-regulated gene inducible nitric oxide synthase (iNOS) in the hyperoxia response was investigated in knock out mice, who had no functional or antiinfarct protection of preconditioning by either hyperoxia or classic ischemic preconditioning. However, neither cardiac iNOS nor contents of antioxidants, heat shock protein 70, or endothelial NOS in the heart increased after hyperoxia. Thus, the signal transduction pathways and organ effectors of hyperoxic protection are not fully determined, but appear to involve MAPK and NFκB. Hyperoxia may have a large potential in the pretreatment of patients undergoing not only open heart procedures, but also in front of any major surgery.
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