Randomization covariates, genetic models were adjusted for population structure using the first f... more Randomization covariates, genetic models were adjusted for population structure using the first five principal components, sex (except in the women-only analyses) and study specific genomic control. Blinding The investigators could not be blinded during data collection and analysis, as case and control cohorts originated from different protocols and/or required a thorough clinical investigation. Reporting for specific materials, systems and methods We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. Materials & experimental systems n/a Involved in the study Antibodies Eukaryotic cell lines Palaeontology and archaeology Animals and other organisms Clinical data Dual use research of concern Methods n/a Involved in the study ChIP-seq Flow cytometry MRI-based neuroimaging
The discovery that cardiac muscle cells can divide until adolescence opens the way to new approac... more The discovery that cardiac muscle cells can divide until adolescence opens the way to new approaches to treating heart disease.
Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the... more Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations-such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-β signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-β receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state Frontiers in Cardiovascular Medicine 01 frontiersin.org
Introduction: Intravascular fibrin clots and extravascular fibrin deposits are often implicated i... more Introduction: Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis. Methods: Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e., locked in the monomeric form), termed Fib AEK mice, and Factor XIII A 2 subunit-deficient mice (FXIII −/−). Female wild-type mice, FXIII −/− mice, and homozygous Fib AEK mice were challenged with carbon tetrachloride (CCl 4), twice weekly for 4 or 6 weeks (1 ml/kg, ip). Results: Hepatic injury and fibrosis induced by CCl 4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in Fib AEK mice).
Frontiers in Cell and Developmental Biology, Oct 11, 2021
Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise fro... more Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise from a variety of diseases, with most resulting in a loss of cardiomyocytes that cannot be replaced due to their inability to replicate, as well as to a lack of resident cardiomyocyte progenitor cells in the adult heart. Identifying and exploiting mechanisms underlying loss of developmental cardiomyocyte replicative capacity has proved to be useful in developing therapeutics to effect adult cardiac regeneration. Of course, effective regeneration of myocardium after injury requires not just expansion of cardiomyocytes, but also neovascularization to allow appropriate perfusion and resolution of injury-induced inflammation and interstitial fibrosis, but also reversal of adverse left ventricular remodeling. In addition to overcoming these challenges, a regenerative therapy needs to be safe and easily translatable. Failure to address these critical issues will delay the translation of regenerative approaches. This review critically analyzes current regenerative approaches while also providing a framework for future experimental studies aimed at enhancing success in regenerating the injured heart.
Recombinant and Cellular Expression of the Murine Chemotactic Protein, CP-10
DNA and Cell Biology, 1994
The S100 protein CP-10 (chemotactic protein, 10 kD), a potent chemotactic factor for murine and h... more The S100 protein CP-10 (chemotactic protein, 10 kD), a potent chemotactic factor for murine and human polymorphonuclear cells (PMN) and murine monocytes, has been purified in small amounts from supernatants of activated murine spleen cells (Lackmann et al., 1992). To obtain a more abundant source of the protein, CP-10 was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST). The property of S100 proteins to undergo calcium-dependent conformational changes was used in a novel approach to optimize the release of recombinant (r) CP-10 by thrombin cleavage. Purified rCP-10 was characterized by amino-terminal sequence analysis and bioassays. Optimal chemotactic activity of rCP-10 for murine PMN and WEHI-265 monocytoid cells was 10(-11) M (native protein has optimal chemotactic activity between 10(-11) and 10(-13) M). Immunization of rabbits with the GST/CP-10 fusion protein bound to glutathione-agarose beads resulted in high titer, specific antibodies that neutralized CP-10-initiated chemotaxis and were suitable for immunoblotting. A combination of Western and Northern analyses identified CP-10 in murine peritoneal exudate PMN and macrophages, splenocytes, bone marrow cells, and WEHI-265 cells (all of myeloid origin), but not in thymus, liver, lung, 3T3 fibroblasts, EL4 lymphoma cells, or bEND 3 brain endothelial cells, indicating cell-specific regulation of CP-10 expression.
Spontaneous Coronary Artery Dissection (SCAD) and a Family History of Aortic Artery Dissection—A Case Series
Heart Lung and Circulation, 2021
SCAD typically affects women in their fifth or sixth decade with a paucity of cardiovascular risk... more SCAD typically affects women in their fifth or sixth decade with a paucity of cardiovascular risk factors.(1) It is caused by a coronary artery intramural haematoma with or without intimal tear. Resultant luminal occlusion manifests as myocardial ischaemia/infarction or death. There are two published sporadic cases of SCAD who developed iatrogenic aortic dissection with coronary angiography.(2, 3) We are not aware of any SCAD cases with intercurrent or historical spontaneous aortic dissection. There is a published SCAD case with a familial history of aortic dissection, in her mother.(4) None of these cases reported a connective tissue disorder. We searched our database of 338 SCAD cases, recruited via social media or cardiologist referral, for cases with a family history of aortic dissection. SCAD diagnosis was confirmed by review of coronary angiogram images by an expert interventional cardiologist blinded to the genetic analysis. Genomic DNA was extracted from buccal cells collected using a cheek swab or mouthwash sample. Whole genome sequencing was performed using the Illumina HiSeq X Ten platform with 30x coverage. These data are being analysed for rare variants in genes associated with familial aortopathies or connective tissue disorders (e.g. FBN1, COL3A1, TGFbR-1/2, SMAD3), as well as for novel gene associations with aortic dissection and/or SCAD. We identified 12 cases with a first- or second-degree relative with aortic dissection. Of these SCAD cases, 11 were female whereas 10 of 12 relatives with aortic dissection were male. In one instance, a maternal uncle, but not the index SCAD case, had Marfan's syndrome. Whole genome sequencing has been performed on the 12 SCAD cases, 2 living relatives with aortic dissection and 2 relatives linking the SCAD and aortic dissection cases. Coronary and aortic dissections have serious consequences and in some families there may be a genetic association between the two conditions. Early identification of variant carriers is critical for disease prevention. Type of funding sources: Foundation. Main funding source(s): This work was supported in part by grants from the Cardiac Society of Australia and New Zealand, the National Health and Medical Research Council, Australia (APP1161200), the St Vincent's Clinic Foundation, the Catholic Archdiocese of Sydney, Perpetual Philanthropy, NSW Health and SCAD Research Inc. LMC is funded by a University Postgraduate Scholarship through University of NSW and a grant from the Avant Foundation.
International Journal of Molecular Sciences, Jul 14, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Randomization covariates, genetic models were adjusted for population structure using the first f... more Randomization covariates, genetic models were adjusted for population structure using the first five principal components, sex (except in the women-only analyses) and study specific genomic control. Blinding The investigators could not be blinded during data collection and analysis, as case and control cohorts originated from different protocols and/or required a thorough clinical investigation. Reporting for specific materials, systems and methods We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. Materials & experimental systems n/a Involved in the study Antibodies Eukaryotic cell lines Palaeontology and archaeology Animals and other organisms Clinical data Dual use research of concern Methods n/a Involved in the study ChIP-seq Flow cytometry MRI-based neuroimaging
The discovery that cardiac muscle cells can divide until adolescence opens the way to new approac... more The discovery that cardiac muscle cells can divide until adolescence opens the way to new approaches to treating heart disease.
Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the... more Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations-such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-β signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-β receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state Frontiers in Cardiovascular Medicine 01 frontiersin.org
Introduction: Intravascular fibrin clots and extravascular fibrin deposits are often implicated i... more Introduction: Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis. Methods: Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e., locked in the monomeric form), termed Fib AEK mice, and Factor XIII A 2 subunit-deficient mice (FXIII −/−). Female wild-type mice, FXIII −/− mice, and homozygous Fib AEK mice were challenged with carbon tetrachloride (CCl 4), twice weekly for 4 or 6 weeks (1 ml/kg, ip). Results: Hepatic injury and fibrosis induced by CCl 4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in Fib AEK mice).
Frontiers in Cell and Developmental Biology, Oct 11, 2021
Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise fro... more Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise from a variety of diseases, with most resulting in a loss of cardiomyocytes that cannot be replaced due to their inability to replicate, as well as to a lack of resident cardiomyocyte progenitor cells in the adult heart. Identifying and exploiting mechanisms underlying loss of developmental cardiomyocyte replicative capacity has proved to be useful in developing therapeutics to effect adult cardiac regeneration. Of course, effective regeneration of myocardium after injury requires not just expansion of cardiomyocytes, but also neovascularization to allow appropriate perfusion and resolution of injury-induced inflammation and interstitial fibrosis, but also reversal of adverse left ventricular remodeling. In addition to overcoming these challenges, a regenerative therapy needs to be safe and easily translatable. Failure to address these critical issues will delay the translation of regenerative approaches. This review critically analyzes current regenerative approaches while also providing a framework for future experimental studies aimed at enhancing success in regenerating the injured heart.
Recombinant and Cellular Expression of the Murine Chemotactic Protein, CP-10
DNA and Cell Biology, 1994
The S100 protein CP-10 (chemotactic protein, 10 kD), a potent chemotactic factor for murine and h... more The S100 protein CP-10 (chemotactic protein, 10 kD), a potent chemotactic factor for murine and human polymorphonuclear cells (PMN) and murine monocytes, has been purified in small amounts from supernatants of activated murine spleen cells (Lackmann et al., 1992). To obtain a more abundant source of the protein, CP-10 was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST). The property of S100 proteins to undergo calcium-dependent conformational changes was used in a novel approach to optimize the release of recombinant (r) CP-10 by thrombin cleavage. Purified rCP-10 was characterized by amino-terminal sequence analysis and bioassays. Optimal chemotactic activity of rCP-10 for murine PMN and WEHI-265 monocytoid cells was 10(-11) M (native protein has optimal chemotactic activity between 10(-11) and 10(-13) M). Immunization of rabbits with the GST/CP-10 fusion protein bound to glutathione-agarose beads resulted in high titer, specific antibodies that neutralized CP-10-initiated chemotaxis and were suitable for immunoblotting. A combination of Western and Northern analyses identified CP-10 in murine peritoneal exudate PMN and macrophages, splenocytes, bone marrow cells, and WEHI-265 cells (all of myeloid origin), but not in thymus, liver, lung, 3T3 fibroblasts, EL4 lymphoma cells, or bEND 3 brain endothelial cells, indicating cell-specific regulation of CP-10 expression.
Spontaneous Coronary Artery Dissection (SCAD) and a Family History of Aortic Artery Dissection—A Case Series
Heart Lung and Circulation, 2021
SCAD typically affects women in their fifth or sixth decade with a paucity of cardiovascular risk... more SCAD typically affects women in their fifth or sixth decade with a paucity of cardiovascular risk factors.(1) It is caused by a coronary artery intramural haematoma with or without intimal tear. Resultant luminal occlusion manifests as myocardial ischaemia/infarction or death. There are two published sporadic cases of SCAD who developed iatrogenic aortic dissection with coronary angiography.(2, 3) We are not aware of any SCAD cases with intercurrent or historical spontaneous aortic dissection. There is a published SCAD case with a familial history of aortic dissection, in her mother.(4) None of these cases reported a connective tissue disorder. We searched our database of 338 SCAD cases, recruited via social media or cardiologist referral, for cases with a family history of aortic dissection. SCAD diagnosis was confirmed by review of coronary angiogram images by an expert interventional cardiologist blinded to the genetic analysis. Genomic DNA was extracted from buccal cells collected using a cheek swab or mouthwash sample. Whole genome sequencing was performed using the Illumina HiSeq X Ten platform with 30x coverage. These data are being analysed for rare variants in genes associated with familial aortopathies or connective tissue disorders (e.g. FBN1, COL3A1, TGFbR-1/2, SMAD3), as well as for novel gene associations with aortic dissection and/or SCAD. We identified 12 cases with a first- or second-degree relative with aortic dissection. Of these SCAD cases, 11 were female whereas 10 of 12 relatives with aortic dissection were male. In one instance, a maternal uncle, but not the index SCAD case, had Marfan's syndrome. Whole genome sequencing has been performed on the 12 SCAD cases, 2 living relatives with aortic dissection and 2 relatives linking the SCAD and aortic dissection cases. Coronary and aortic dissections have serious consequences and in some families there may be a genetic association between the two conditions. Early identification of variant carriers is critical for disease prevention. Type of funding sources: Foundation. Main funding source(s): This work was supported in part by grants from the Cardiac Society of Australia and New Zealand, the National Health and Medical Research Council, Australia (APP1161200), the St Vincent's Clinic Foundation, the Catholic Archdiocese of Sydney, Perpetual Philanthropy, NSW Health and SCAD Research Inc. LMC is funded by a University Postgraduate Scholarship through University of NSW and a grant from the Avant Foundation.
International Journal of Molecular Sciences, Jul 14, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
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