kathryn smedlund - Academia.edu (original) (raw)
Papers by kathryn smedlund
Cardiovascular & Hematological Agents in Medicinal Chemistry, 2012
In endothelium, calcium (Ca 2+) influx through plasma membrane Ca 2+-permeable channels plays a f... more In endothelium, calcium (Ca 2+) influx through plasma membrane Ca 2+-permeable channels plays a fundamental role in several physiological functions and in the pathogenesis of cardiovascular disease. Current knowledge on the influence of Ca 2+ influx in signaling events associated to endothelial dysfunction has grown significantly over recent years, particularly after identification of members of the Transient Receptor Potential Canonical (TRPC) family of channel forming proteins as prominent mediators of Ca 2+ entry in endothelial cells. Among TRPC members TRPC3 has been at the center of many of these physiopathological processes. Progress in elucidating the mechanism/s underlying regulation of endothelial TRPC3 and characterization of signaling events downstream TRPC3 activation are of most importance to fully appreciate the role of this peculiar cation channel in cardiovascular disease and its potential use as a therapeutic target. In this updated review we focus on TRPC3 channels, revising and discussing current knowledge on channel expression and regulation in endothelium and the roles of TRPC3 in cardiovascular disease in relation to endothelial dysfunction.
Background—Vascular cell adhesion molecule-1 (VCAM-1) is critical in monocyte recruitment to the ... more Background—Vascular cell adhesion molecule-1 (VCAM-1) is critical in monocyte recruitment to the endothelium, a key event in development of atherosclerotic lesions. Stimulation of human coronary artery endothelial cells (HCAECs) with ATP positively modulates VCAM-1 expression and function through a mechanism involving Ca signaling. We here examined the role of Ca influx and native TRPC3 channels in that mechanism. Methods and Results—Omission of extracellular Ca or pretreatment of cells with channel blockers markedly reduced ATP-induced VCAM-1 and monocyte adhesion. Using a siRNA strategy and real-time fluorescence, we found that native TRPC3 proteins contribute to constitutive and ATP-regulated Ca influx. ATP-dependent upregulation of VCAM-1 was accompanied by an increase in basal cation entry and TRPC3 expression. Notably, TRPC3 knock-down resulted in a dramatic reduction of ATP-induced VCAM-1 and monocyte adhesion. Conclusions—These findings indicate that in HCAECs, native TRPC3 ...
Trends in Endocrinology & Metabolism
The molecular chaperone FK506-binding protein 51 (FKBP51) is gaining attention as a meaningful bi... more The molecular chaperone FK506-binding protein 51 (FKBP51) is gaining attention as a meaningful biomarker of metabolic dysfunction. This review examines the emerging contributions of FKBP51 in adipogenesis and lipid metabolism, myogenesis and protein catabolism, and glucocorticoid-induced skin hypoplasia and dermal adipocytes. The FKBP51 signaling mechanisms that may explain these metabolic consequences are discussed. These mechanisms are diverse, with FKBP51 independently and directly regulating phosphorylation cascades and nuclear receptors. We provide a discussion of the newly developed compounds that antagonize FKBP51, which may offer therapeutic advantages for adiposity. These observations suggest we are only beginning to uncover the complex nature of FKBP51 and its molecular chaperoning of metabolism.
Physiological Genomics
A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous ... more A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a “spike” protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outc...
Molecular and Cellular Endocrinology
Advances in Experimental Medicine and Biology, 2016
In the cardiovascular and hematopoietic systems the Transient Receptor Potential Canonical 3 (TRP... more In the cardiovascular and hematopoietic systems the Transient Receptor Potential Canonical 3 (TRPC3) channel has a well-recognized role in a number of signaling mechanisms that impact the function of diverse cells and tissues in physiology and disease. The latter includes, but is not limited to, molecular and cellular mechanisms associated to the pathogenesis of cardiac hypertrophy, hypertension and endothelial dysfunction. Despite several of these functions being closely related to atherorelevant mechanisms, the potential roles of TRPC3 in atherosclerosis, the major cause of coronary artery disease, have remained largely unexplored. Over recent years, a series of studies from the authors' laboratory revealed novel functions of TRPC3 in mechanisms related to endothelial inflammation, monocyte adhesion to endothelium and survival and apoptosis of macrophages. The relevance of these new TRPC3 functions to atherogenesis has recently began to receive validation through studies in mouse models of atherosclerosis with conditional gain or loss of TRPC3 function. This chapter summarizes these novel findings and provides a discussion of their impact in the context of atherosclerosis, in an attempt to delineate a framework for further exploration of this terra incognita in the TRPC field.
...............................................................................................ii... more ...............................................................................................iii Dedication.............................................................................................vi Acknowledgments..................................................................................vii Table of
Vascular Pharmacology, 2015
Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the un... more Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the unfolded protein response (UPR) is a well-recognized mechanism of endothelial cell apoptosis with a major impact on the integrity of the endothelium during the course of cardiovascular diseases. As in other cell types, Ca(2+) influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated with it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca(2+)-permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca(2+) influx which is critical for operation of inflammatory signaling in these cells, through a mechanism that entails coupling of TRPC3 constitutive function to activation of Ca(2+)/calmodulin-dependent protein kinase II (CAMKII). TRPC3 has been linked to UPR signaling and apoptosis in cells other than endothelial, and CAMKII is a mediator of ER stress-induced apoptosis in various cell types, including endothelial cells. In the present work we used a pharmacological approach to examine whether in HCAECs TRPC3 and CAMKII also contribute to mechanisms of ER stress-induced apoptosis. The findings show for the first time that in HCAECs activation of the UPR and the subsequent ER stress-induced apoptosis exhibit a strong requirement for constitutive Ca(2+) influx and that TRPC3 contributes to this process. In addition, we obtained evidence indicating that, similar to its roles in non-endothelial cells, CAMKII participates in ER stress-induced apoptosis in HCAECs.
Coronary Artery Disease - New Insights and Novel Approaches, 2012
Introduction 1.1 Endothelial inflammatory signaling and monocyte recruitment Recruitment of circu... more Introduction 1.1 Endothelial inflammatory signaling and monocyte recruitment Recruitment of circulating monocytes to activated areas of the endothelium and their migration to the subintimal inflammatory foci represents one of the earliest events in atherogenesis (Linton and Fazio 2003; Hansson 2005). Importantly, monocyte recruitment can be recognized throughout all lesional stages including advanced lesions, where plaque infiltration and neovascularization occur. Indeed, available experimental evidence supports the notion that in advanced stages monocyte infiltration contributes to plaque instability and rupture (Virmani, Burke et al. 2006). Monocyte recruitment to the subendothelial milieu implies a sequence of events that begin with monocyte rolling along and tethering to the endothelial surface, firm adhesion and activation, and ultimately migration to the subintima. At the molecular level, the entire sequence entails interaction of integrins on the monocyte surface with cell adhesion molecules (CAMs) expressed on the endothelial cell. Monocyte rolling and tethering is mainly mediated by CAMs from the selectin group (v.g., E-selectin) while firm adhesion and migration are mostly mediated by CAMs from the immunoglobulin (Ig) superfamily, such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Compelling evidence accumulated over the last decade has clearly established that VCAM-1 (CD106) has a prominent role in mediating attachment and migration of monocytes (the Cluster of Differentiation nomenclature (Zola, Swart et al. 2005) is given for reference, but "VCAM-1" will be used throughout the text). 1.1.1 VCAM-1 expression and atherosclerosis Although other adhesion molecules, such as ICAM-1 (CD54) or E-selectin, also contribute to adhesion of monocytes to endothelial cells, VCAM-1 is unique in that its expression level and pattern are highly sensitive to the action of several pro-inflammatory/proatherogenic stimuli. While other CAMs are constitutively expressed in non-activated www.intechopen.com
Proceedings of the National Academy of Sciences of the United States of America, Jan 13, 2015
In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a ... more In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expression in these cells was found to be up-regulated by proatherogenic factors, which enhanced inflammation and VCAM-1 expression. However, it remained to be determined whether these in vitro findings were of relevance to atherosclerotic lesion development in vivo. To answer this important question in the present work, we generated mice with endothelial-specific overexpression of human TRPC3 in an Apoe knockout background (TgEST3ApoeKO) and examined lesions in the aortic sinus following 10 and 16 wk on a high-fat diet. No significant differences were found in size or complexity of early stage lesion...
users to download, copy and build upon published articles even for commercial purposes, as long a... more users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.
Cardiovascular & Hematological Agents in Medicinal Chemistry (formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents), 2010
An impressive amount of experimental evidence accumulated over the last two decades has clearly d... more An impressive amount of experimental evidence accumulated over the last two decades has clearly demonstrated that Ca(2+) influx through plasma membrane Ca(2+)-permeable channels plays a critical role in endothelial cell physiology and pathophysiology. Research efforts aimed at understanding the role of Ca(2+) influx within the signaling events underlying endothelial dysfunction have grown at a fast pace over more recent years. Transient Receptor Potential Canonical (TRPC) proteins, which belong to the larger TRP superfamily of channel forming proteins, form Ca(2+)-permeable cation channels in vascular endothelium and there is currently no question about their involvement in Ca(2+) influx associated with endothelial cell's physiology. It is also becoming evident that TRPCs are important players in the pathogenesis of cardiovascular disease. Therefore, it is imperative to elucidate the mechanism/s underlying regulation of endothelial TRPC channels as well as to identify signaling events downstream TRPC activation in order to better comprehend their role in cardiovascular physiology and disease. This review focuses on members of the TRPC3/6/7 group of TRPC proteins, revises current knowledge on their expression and regulation in endothelium, and discusses their role in cardiovascular disease as it relates to endothelial dysfunction.
Cardiovascular & Hematological Agents in Medicinal Chemistry, 2012
In endothelium, calcium (Ca 2+) influx through plasma membrane Ca 2+-permeable channels plays a f... more In endothelium, calcium (Ca 2+) influx through plasma membrane Ca 2+-permeable channels plays a fundamental role in several physiological functions and in the pathogenesis of cardiovascular disease. Current knowledge on the influence of Ca 2+ influx in signaling events associated to endothelial dysfunction has grown significantly over recent years, particularly after identification of members of the Transient Receptor Potential Canonical (TRPC) family of channel forming proteins as prominent mediators of Ca 2+ entry in endothelial cells. Among TRPC members TRPC3 has been at the center of many of these physiopathological processes. Progress in elucidating the mechanism/s underlying regulation of endothelial TRPC3 and characterization of signaling events downstream TRPC3 activation are of most importance to fully appreciate the role of this peculiar cation channel in cardiovascular disease and its potential use as a therapeutic target. In this updated review we focus on TRPC3 channels, revising and discussing current knowledge on channel expression and regulation in endothelium and the roles of TRPC3 in cardiovascular disease in relation to endothelial dysfunction.
Background—Vascular cell adhesion molecule-1 (VCAM-1) is critical in monocyte recruitment to the ... more Background—Vascular cell adhesion molecule-1 (VCAM-1) is critical in monocyte recruitment to the endothelium, a key event in development of atherosclerotic lesions. Stimulation of human coronary artery endothelial cells (HCAECs) with ATP positively modulates VCAM-1 expression and function through a mechanism involving Ca signaling. We here examined the role of Ca influx and native TRPC3 channels in that mechanism. Methods and Results—Omission of extracellular Ca or pretreatment of cells with channel blockers markedly reduced ATP-induced VCAM-1 and monocyte adhesion. Using a siRNA strategy and real-time fluorescence, we found that native TRPC3 proteins contribute to constitutive and ATP-regulated Ca influx. ATP-dependent upregulation of VCAM-1 was accompanied by an increase in basal cation entry and TRPC3 expression. Notably, TRPC3 knock-down resulted in a dramatic reduction of ATP-induced VCAM-1 and monocyte adhesion. Conclusions—These findings indicate that in HCAECs, native TRPC3 ...
Trends in Endocrinology & Metabolism
The molecular chaperone FK506-binding protein 51 (FKBP51) is gaining attention as a meaningful bi... more The molecular chaperone FK506-binding protein 51 (FKBP51) is gaining attention as a meaningful biomarker of metabolic dysfunction. This review examines the emerging contributions of FKBP51 in adipogenesis and lipid metabolism, myogenesis and protein catabolism, and glucocorticoid-induced skin hypoplasia and dermal adipocytes. The FKBP51 signaling mechanisms that may explain these metabolic consequences are discussed. These mechanisms are diverse, with FKBP51 independently and directly regulating phosphorylation cascades and nuclear receptors. We provide a discussion of the newly developed compounds that antagonize FKBP51, which may offer therapeutic advantages for adiposity. These observations suggest we are only beginning to uncover the complex nature of FKBP51 and its molecular chaperoning of metabolism.
Physiological Genomics
A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous ... more A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a “spike” protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outc...
Molecular and Cellular Endocrinology
Advances in Experimental Medicine and Biology, 2016
In the cardiovascular and hematopoietic systems the Transient Receptor Potential Canonical 3 (TRP... more In the cardiovascular and hematopoietic systems the Transient Receptor Potential Canonical 3 (TRPC3) channel has a well-recognized role in a number of signaling mechanisms that impact the function of diverse cells and tissues in physiology and disease. The latter includes, but is not limited to, molecular and cellular mechanisms associated to the pathogenesis of cardiac hypertrophy, hypertension and endothelial dysfunction. Despite several of these functions being closely related to atherorelevant mechanisms, the potential roles of TRPC3 in atherosclerosis, the major cause of coronary artery disease, have remained largely unexplored. Over recent years, a series of studies from the authors' laboratory revealed novel functions of TRPC3 in mechanisms related to endothelial inflammation, monocyte adhesion to endothelium and survival and apoptosis of macrophages. The relevance of these new TRPC3 functions to atherogenesis has recently began to receive validation through studies in mouse models of atherosclerosis with conditional gain or loss of TRPC3 function. This chapter summarizes these novel findings and provides a discussion of their impact in the context of atherosclerosis, in an attempt to delineate a framework for further exploration of this terra incognita in the TRPC field.
...............................................................................................ii... more ...............................................................................................iii Dedication.............................................................................................vi Acknowledgments..................................................................................vii Table of
Vascular Pharmacology, 2015
Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the un... more Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the unfolded protein response (UPR) is a well-recognized mechanism of endothelial cell apoptosis with a major impact on the integrity of the endothelium during the course of cardiovascular diseases. As in other cell types, Ca(2+) influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated with it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca(2+)-permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca(2+) influx which is critical for operation of inflammatory signaling in these cells, through a mechanism that entails coupling of TRPC3 constitutive function to activation of Ca(2+)/calmodulin-dependent protein kinase II (CAMKII). TRPC3 has been linked to UPR signaling and apoptosis in cells other than endothelial, and CAMKII is a mediator of ER stress-induced apoptosis in various cell types, including endothelial cells. In the present work we used a pharmacological approach to examine whether in HCAECs TRPC3 and CAMKII also contribute to mechanisms of ER stress-induced apoptosis. The findings show for the first time that in HCAECs activation of the UPR and the subsequent ER stress-induced apoptosis exhibit a strong requirement for constitutive Ca(2+) influx and that TRPC3 contributes to this process. In addition, we obtained evidence indicating that, similar to its roles in non-endothelial cells, CAMKII participates in ER stress-induced apoptosis in HCAECs.
Coronary Artery Disease - New Insights and Novel Approaches, 2012
Introduction 1.1 Endothelial inflammatory signaling and monocyte recruitment Recruitment of circu... more Introduction 1.1 Endothelial inflammatory signaling and monocyte recruitment Recruitment of circulating monocytes to activated areas of the endothelium and their migration to the subintimal inflammatory foci represents one of the earliest events in atherogenesis (Linton and Fazio 2003; Hansson 2005). Importantly, monocyte recruitment can be recognized throughout all lesional stages including advanced lesions, where plaque infiltration and neovascularization occur. Indeed, available experimental evidence supports the notion that in advanced stages monocyte infiltration contributes to plaque instability and rupture (Virmani, Burke et al. 2006). Monocyte recruitment to the subendothelial milieu implies a sequence of events that begin with monocyte rolling along and tethering to the endothelial surface, firm adhesion and activation, and ultimately migration to the subintima. At the molecular level, the entire sequence entails interaction of integrins on the monocyte surface with cell adhesion molecules (CAMs) expressed on the endothelial cell. Monocyte rolling and tethering is mainly mediated by CAMs from the selectin group (v.g., E-selectin) while firm adhesion and migration are mostly mediated by CAMs from the immunoglobulin (Ig) superfamily, such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Compelling evidence accumulated over the last decade has clearly established that VCAM-1 (CD106) has a prominent role in mediating attachment and migration of monocytes (the Cluster of Differentiation nomenclature (Zola, Swart et al. 2005) is given for reference, but "VCAM-1" will be used throughout the text). 1.1.1 VCAM-1 expression and atherosclerosis Although other adhesion molecules, such as ICAM-1 (CD54) or E-selectin, also contribute to adhesion of monocytes to endothelial cells, VCAM-1 is unique in that its expression level and pattern are highly sensitive to the action of several pro-inflammatory/proatherogenic stimuli. While other CAMs are constitutively expressed in non-activated www.intechopen.com
Proceedings of the National Academy of Sciences of the United States of America, Jan 13, 2015
In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a ... more In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expression in these cells was found to be up-regulated by proatherogenic factors, which enhanced inflammation and VCAM-1 expression. However, it remained to be determined whether these in vitro findings were of relevance to atherosclerotic lesion development in vivo. To answer this important question in the present work, we generated mice with endothelial-specific overexpression of human TRPC3 in an Apoe knockout background (TgEST3ApoeKO) and examined lesions in the aortic sinus following 10 and 16 wk on a high-fat diet. No significant differences were found in size or complexity of early stage lesion...
users to download, copy and build upon published articles even for commercial purposes, as long a... more users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.
Cardiovascular & Hematological Agents in Medicinal Chemistry (formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents), 2010
An impressive amount of experimental evidence accumulated over the last two decades has clearly d... more An impressive amount of experimental evidence accumulated over the last two decades has clearly demonstrated that Ca(2+) influx through plasma membrane Ca(2+)-permeable channels plays a critical role in endothelial cell physiology and pathophysiology. Research efforts aimed at understanding the role of Ca(2+) influx within the signaling events underlying endothelial dysfunction have grown at a fast pace over more recent years. Transient Receptor Potential Canonical (TRPC) proteins, which belong to the larger TRP superfamily of channel forming proteins, form Ca(2+)-permeable cation channels in vascular endothelium and there is currently no question about their involvement in Ca(2+) influx associated with endothelial cell's physiology. It is also becoming evident that TRPCs are important players in the pathogenesis of cardiovascular disease. Therefore, it is imperative to elucidate the mechanism/s underlying regulation of endothelial TRPC channels as well as to identify signaling events downstream TRPC activation in order to better comprehend their role in cardiovascular physiology and disease. This review focuses on members of the TRPC3/6/7 group of TRPC proteins, revises current knowledge on their expression and regulation in endothelium, and discusses their role in cardiovascular disease as it relates to endothelial dysfunction.