Adrian Thomson - Academia.edu (original) (raw)

Papers by Adrian Thomson

Human Molecular Genetics, 2013

Hypertension

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the en... more GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ′5538. In male wild-type mice, intravenous AZ′5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ′5538 had no effect on blood pressure or renal hemodynamics in Gpr81 −/− mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ′553...

Circulation Research

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved... more Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodeling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). Objectives: To investigate the role of lncRNAs in EndMT and their relevance to vascular remodeling. Methods and Results: To study EndMT in vitro, primary endothelial cells were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-seq (RNA-sequencing) were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA (dicer-substrate short interfering RNAs) screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human endothelial cell types undergoing EndMT in vitro. MIR503HG depletion induced a spontane...

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. W... more Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line. We investigated post-natal growth and development, basal cardiac function, the cardiac functional response and tissue-specific response to myocardial infarction. To investigate the contribution of the LINC00961/SPAAR locus to determination of longitudinal growth, cardiac function, and response to myocardial infarction, we used a novel CRISPR/Cas9 locus knockout mouse line. Data mining suggested that SPAAR is predominantly expressed in human cardiac endothelial cells and fibroblasts, while murine LINC00961 expression is hypoxia-responsive in...

JACC: Basic to Translational Science

Journal of Hepatology

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.

Frontiers in Physiology

Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidi... more Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of preclinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intrarenal inflammation revealed persistent recruitment of Ly6C hi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, singlestep flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.

Ultrasound in Medicine & Biology

Echo Research and Practice

A technology based on velocity ratio indices is described for application in the myocardium. Angl... more A technology based on velocity ratio indices is described for application in the myocardium. Angle-independent Doppler indices, such as the Pulsatility Index, which employ velocity ratios, can be measured even if the ultrasound beam vector at the moving target and the motion vector are not in a known plane. The unknown plane situation is often encountered when an ultrasound beam interrogates sites in the myocardium. The velocities employed in an index calculation must be close to the same or opposite directions. The Doppler velocity ratio indices are independent of angle in 3D space as are ratios indices based on 1D Strain and 1D Speckle Tracking. Angle-independent results with spectral Doppler methods are discussed. Possible future imaging techniques based on velocity ratios are presented. By using indices that involve ratios, several other sources of error cancel in addition to that of angular dependence e.g. errors due to less than optimum gain settings and beam distortion. This ...

Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophil... more Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings. Objectives: To investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI. Methods: Blood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice (ΔdblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests. Results: Blood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0 ± 2.2cm2 v 21.6 ± 1.6cm2;...

Clinical & Experimental Immunology

Activation of the innate immune response following myocardial infarction (MI) is essential for in... more Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1-dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2-dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12-15-week-old male wild-type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206 + anti-inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6C high monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6C high monocytosis, splenic Ly6C high monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti-inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post-MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

Journal of Endocrinology

Endogenous glucocorticoid action is important in the structural and functional maturation of the ... more Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5-E15.5. To test direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affecte...

Science Signaling

Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs,... more Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1–AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK...

Ultrasound in medicine & biology, Mar 1, 2018

Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties ... more Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12-32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate-buffered saline solution maintained at 37.2 ± 0.2 °C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidn...

Journal of the American College of Cardiology

Hypertension (Dallas, Tex. : 1979), Jan 24, 2017

CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabe... more CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb(-/-) rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb(-/-) rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and car...

The Journal of endocrinology, Mar 1, 2017

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis ... more Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left vent...

Human Molecular Genetics, 2013

Hypertension

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the en... more GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ′5538. In male wild-type mice, intravenous AZ′5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ′5538 had no effect on blood pressure or renal hemodynamics in Gpr81 −/− mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ′553...

Circulation Research

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved... more Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodeling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). Objectives: To investigate the role of lncRNAs in EndMT and their relevance to vascular remodeling. Methods and Results: To study EndMT in vitro, primary endothelial cells were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-seq (RNA-sequencing) were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA (dicer-substrate short interfering RNAs) screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human endothelial cell types undergoing EndMT in vitro. MIR503HG depletion induced a spontane...

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. W... more Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line. We investigated post-natal growth and development, basal cardiac function, the cardiac functional response and tissue-specific response to myocardial infarction. To investigate the contribution of the LINC00961/SPAAR locus to determination of longitudinal growth, cardiac function, and response to myocardial infarction, we used a novel CRISPR/Cas9 locus knockout mouse line. Data mining suggested that SPAAR is predominantly expressed in human cardiac endothelial cells and fibroblasts, while murine LINC00961 expression is hypoxia-responsive in...

JACC: Basic to Translational Science

Journal of Hepatology

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.

Frontiers in Physiology

Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidi... more Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of preclinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intrarenal inflammation revealed persistent recruitment of Ly6C hi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, singlestep flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.

Ultrasound in Medicine & Biology

Echo Research and Practice

A technology based on velocity ratio indices is described for application in the myocardium. Angl... more A technology based on velocity ratio indices is described for application in the myocardium. Angle-independent Doppler indices, such as the Pulsatility Index, which employ velocity ratios, can be measured even if the ultrasound beam vector at the moving target and the motion vector are not in a known plane. The unknown plane situation is often encountered when an ultrasound beam interrogates sites in the myocardium. The velocities employed in an index calculation must be close to the same or opposite directions. The Doppler velocity ratio indices are independent of angle in 3D space as are ratios indices based on 1D Strain and 1D Speckle Tracking. Angle-independent results with spectral Doppler methods are discussed. Possible future imaging techniques based on velocity ratios are presented. By using indices that involve ratios, several other sources of error cancel in addition to that of angular dependence e.g. errors due to less than optimum gain settings and beam distortion. This ...

Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophil... more Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings. Objectives: To investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI. Methods: Blood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice (ΔdblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests. Results: Blood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0 ± 2.2cm2 v 21.6 ± 1.6cm2;...

Clinical & Experimental Immunology

Activation of the innate immune response following myocardial infarction (MI) is essential for in... more Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1-dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2-dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12-15-week-old male wild-type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206 + anti-inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6C high monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6C high monocytosis, splenic Ly6C high monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti-inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post-MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

Journal of Endocrinology

Endogenous glucocorticoid action is important in the structural and functional maturation of the ... more Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5-E15.5. To test direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affecte...

Science Signaling

Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs,... more Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1–AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK...

Ultrasound in medicine & biology, Mar 1, 2018

Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties ... more Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12-32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate-buffered saline solution maintained at 37.2 ± 0.2 °C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidn...

Journal of the American College of Cardiology

Hypertension (Dallas, Tex. : 1979), Jan 24, 2017

CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabe... more CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb(-/-) rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb(-/-) rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and car...

The Journal of endocrinology, Mar 1, 2017

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis ... more Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left vent...