Susie Butler - Academia.edu (original) (raw)
Papers by Susie Butler
Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids i... more Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids in regulating cellular functions. Cholesterol of the vascular endothelial cell (EC) membranes is also being recognized as an important element in the vascular EC signaling. However, methods utilized in studying the important role of lipid raft-associated cholesterol in cell signaling involve removal of the raft cholesterol with the aid of chemical agents called cyclodextrins. Caution should be exercised in using cyclodextrins to remove the cellular lipid raft-associated cholesterol as the cyclodextrins cause adverse effects on cells such as loss of cell viability or induction of cytotoxicity. Therefore, the choice of a cyclodextrin to remove the cellular lipid raft-associated cholesterol is extremely important in order to ensure effective and safe removal of cholesterol from the cellular lipid rafts. In order to achieve this, here, we have selected the bovine pulmonary artery endothelial ...
International Journal of Toxicology, 2009
Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, act... more Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, activates vascular endothelial cell (EC) phospholipase D (PLD). Here, we report the novel and significant finding that calcium and calmodulin regulated mercury-induced PLD activation in bovine pulmonary artery ECs (BPAECs). Mercury (mercury chloride, 25 mM; thimerosal, 25 mM; methylmercury, 10 mM) significantly activated PLD in BPAECs. Calcium chelating agents and calcium depletion of the medium completely attenuated the mercury-induced PLD activation in ECs. Calmodulin inhibitors significantly attenuated mercury-induced PLD activation in BPAECs. Despite the absence of L-type calcium channels in ECs, nifedipine, nimodipine, and diltiazem significantly attenuated mercury-induced PLD activation and cytotoxicity in BPAECs. This study demonstrated the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the protective action of L-type calcium channel blockers against mercury cytotoxicity in vascular ECs, suggesting mechanisms of mercury vasculotoxicity and mercury-induced cardiovascular diseases.
Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids i... more Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids in regulating cellular functions. Cholesterol of the vascular endothelial cell (EC) membranes is also being recognized as an important element in the vascular EC signaling. However, methods utilized in studying the important role of lipid raft-associated cholesterol in cell signaling involve removal of the raft cholesterol with the aid of chemical agents called cyclodextrins. Caution should be exercised in using cyclodextrins to remove the cellular lipid raft-associated cholesterol as the cyclodextrins cause adverse effects on cells such as loss of cell viability or induction of cytotoxicity. Therefore, the choice of a cyclodextrin to remove the cellular lipid raft-associated cholesterol is extremely important in order to ensure effective and safe removal of cholesterol from the cellular lipid rafts. In order to achieve this, here, we have selected the bovine pulmonary artery endothelial cells (BPAECs) and subjected them to the removal of cholesterol using two different beta-cyclodextrin compounds, methyl-beta-cyclodextrin (MbetaCD) and hydroxypropyl-beta-cyclodextrin (HPCD). Phospholipase D (PLD), which generates one of the most potent bioactive lipid signal mediators (phosphatidic acid), is activated by oxidants. Therefore, we examined the effects of cholesterol removal by utilizing our current methods on the hydrogen peroxide (H(2)O(2))-activated PLD in BPAECs. Differences in the loss of cholesterol and the resulting effects on the cell membrane, cell viability, morphology, and the extent of oxidant-induced PLD activation were determined. The results revealed that both MbetaCD and HPCD caused loss of cholesterol, loss of cell viability, and altered cell morphology in the chosen EC system. It was also determined that the HPCD compound caused far less extensive damage to the cells than the MbetaCD, therefore making the HPCD compound a safer tool for EC cholesterol removal.
International Journal of Toxicology, 2009
Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, act... more Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, activates vascular endothelial cell (EC) phospholipase D (PLD). Here, we report the novel and significant finding that calcium and calmodulin regulated mercury-induced PLD activation in bovine pulmonary artery ECs (BPAECs). Mercury (mercury chloride, 25 mM; thimerosal, 25 mM; methylmercury, 10 mM) significantly activated PLD in BPAECs. Calcium chelating agents and calcium depletion of the medium completely attenuated the mercury-induced PLD activation in ECs. Calmodulin inhibitors significantly attenuated mercury-induced PLD activation in BPAECs. Despite the absence of L-type calcium channels in ECs, nifedipine, nimodipine, and diltiazem significantly attenuated mercury-induced PLD activation and cytotoxicity in BPAECs. This study demonstrated the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the protective action of L-type calcium channel blockers against mercury cytotoxicity in vascular ECs, suggesting mechanisms of mercury vasculotoxicity and mercury-induced cardiovascular diseases.
B73. SLEEP DISORDERED BREATHING AND CONTROL OF VENTILATION: BASIC AND TRANSLATIONAL ASPECTS, 2010
ABSTRACT
Toxicological Sciences, 2010
Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As a ... more Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. It is also a major component of cigarette smoke, and its inhalation is associated with decreased pulmonary function, lung cancer, and chronic obstructive pulmonary disease. Ion channels, including the cystic fibrosis transmembrane conductance regulator (CFTR), play a central role in maintaining fluid homeostasis and lung functions. CFTR is mostly expressed in epithelial cells, and little is known about the effect of cadmium exposure on lung epithelial cell function. We show that exposure to cadmium decreases the expression of the CFTR protein and subsequent chloride transport in human airway epithelial cells in vitro. Impairment of CFTR protein expression was also observed in vivo in the lung of mice after intranasal instillation of cadmium. We established that the inhibitory effect of cadmium was not a nonspecific effect of heavy metals, as nickel had no effect on CFTR protein levels. Finally, we show that selected antioxidants, including alpha-tocopherol (vitamin E), but not N-acetylcysteine, can prevent the cadmiuminduced suppression of CFTR. In summary, we have identified cadmium as a regulator of the CFTR chloride channel present in lung epithelial cells. Future strategies to prevent the deleterious effect of cadmium on epithelial cells and lung functions may benefit from the finding that alpha-tocopherol protects CFTR expression and function.
Molecular and Cellular Biochemistry, 2010
Vascular endothelium is vulnerable to the attack of glucose-derived oxoaldehydes (glyoxal and met... more Vascular endothelium is vulnerable to the attack of glucose-derived oxoaldehydes (glyoxal and methylglyoxal) during diabetes, through the formation of advanced glycation end products (AGEs). Although aminoguanidine (AG) has been shown to protect against the AGE-induced adverse effects, its protection against the glyoxal-induced alterations in vascular endothelial cells (ECs) such as cytotoxicity, barrier dysfunction, and inhibition of angiogenesis has not been reported and we investigated this in the bovine pulmonary artery ECs (BPAECs). The results showed that glyoxal (1-10 mM) significantly induced cytotoxicity and mitochondrial dysfunction in a dose-and time-dependent (4-12 h) fashion in ECs. Glyoxal was also observed to significantly inhibit EC proliferation. The study also revealed that glyoxal induced EC barrier dysfunction (loss of trans-endothelial electrical resistance), actin cytoskeletal rearrangement, and tight junction alterations in BPAECs. Furthermore, the results revealed that glyoxal significantly inhibited in vitro angiogenesis on the Matrigel. For the first time, this study demonstrated that AG significantly protected against the glyoxal-induced cytotoxicity, barrier dysfunction, cytoskeletal rearrangement, and inhibition of angiogenesis in BPAECs. Therefore, AG appears as a promising protective agent in the treatment of AGE-induced vascular endothelial alterations and dysfunction during diabetes, presumably by blocking the reactivity of the sugar-derived dicarbonyls such as glyoxal and preventing the formation of AGEs.
Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids i... more Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids in regulating cellular functions. Cholesterol of the vascular endothelial cell (EC) membranes is also being recognized as an important element in the vascular EC signaling. However, methods utilized in studying the important role of lipid raft-associated cholesterol in cell signaling involve removal of the raft cholesterol with the aid of chemical agents called cyclodextrins. Caution should be exercised in using cyclodextrins to remove the cellular lipid raft-associated cholesterol as the cyclodextrins cause adverse effects on cells such as loss of cell viability or induction of cytotoxicity. Therefore, the choice of a cyclodextrin to remove the cellular lipid raft-associated cholesterol is extremely important in order to ensure effective and safe removal of cholesterol from the cellular lipid rafts. In order to achieve this, here, we have selected the bovine pulmonary artery endothelial ...
International Journal of Toxicology, 2009
Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, act... more Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, activates vascular endothelial cell (EC) phospholipase D (PLD). Here, we report the novel and significant finding that calcium and calmodulin regulated mercury-induced PLD activation in bovine pulmonary artery ECs (BPAECs). Mercury (mercury chloride, 25 mM; thimerosal, 25 mM; methylmercury, 10 mM) significantly activated PLD in BPAECs. Calcium chelating agents and calcium depletion of the medium completely attenuated the mercury-induced PLD activation in ECs. Calmodulin inhibitors significantly attenuated mercury-induced PLD activation in BPAECs. Despite the absence of L-type calcium channels in ECs, nifedipine, nimodipine, and diltiazem significantly attenuated mercury-induced PLD activation and cytotoxicity in BPAECs. This study demonstrated the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the protective action of L-type calcium channel blockers against mercury cytotoxicity in vascular ECs, suggesting mechanisms of mercury vasculotoxicity and mercury-induced cardiovascular diseases.
Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids i... more Lipid raft-associated cholesterol has been identified as a pivotal player among membrane lipids in regulating cellular functions. Cholesterol of the vascular endothelial cell (EC) membranes is also being recognized as an important element in the vascular EC signaling. However, methods utilized in studying the important role of lipid raft-associated cholesterol in cell signaling involve removal of the raft cholesterol with the aid of chemical agents called cyclodextrins. Caution should be exercised in using cyclodextrins to remove the cellular lipid raft-associated cholesterol as the cyclodextrins cause adverse effects on cells such as loss of cell viability or induction of cytotoxicity. Therefore, the choice of a cyclodextrin to remove the cellular lipid raft-associated cholesterol is extremely important in order to ensure effective and safe removal of cholesterol from the cellular lipid rafts. In order to achieve this, here, we have selected the bovine pulmonary artery endothelial cells (BPAECs) and subjected them to the removal of cholesterol using two different beta-cyclodextrin compounds, methyl-beta-cyclodextrin (MbetaCD) and hydroxypropyl-beta-cyclodextrin (HPCD). Phospholipase D (PLD), which generates one of the most potent bioactive lipid signal mediators (phosphatidic acid), is activated by oxidants. Therefore, we examined the effects of cholesterol removal by utilizing our current methods on the hydrogen peroxide (H(2)O(2))-activated PLD in BPAECs. Differences in the loss of cholesterol and the resulting effects on the cell membrane, cell viability, morphology, and the extent of oxidant-induced PLD activation were determined. The results revealed that both MbetaCD and HPCD caused loss of cholesterol, loss of cell viability, and altered cell morphology in the chosen EC system. It was also determined that the HPCD compound caused far less extensive damage to the cells than the MbetaCD, therefore making the HPCD compound a safer tool for EC cholesterol removal.
International Journal of Toxicology, 2009
Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, act... more Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, activates vascular endothelial cell (EC) phospholipase D (PLD). Here, we report the novel and significant finding that calcium and calmodulin regulated mercury-induced PLD activation in bovine pulmonary artery ECs (BPAECs). Mercury (mercury chloride, 25 mM; thimerosal, 25 mM; methylmercury, 10 mM) significantly activated PLD in BPAECs. Calcium chelating agents and calcium depletion of the medium completely attenuated the mercury-induced PLD activation in ECs. Calmodulin inhibitors significantly attenuated mercury-induced PLD activation in BPAECs. Despite the absence of L-type calcium channels in ECs, nifedipine, nimodipine, and diltiazem significantly attenuated mercury-induced PLD activation and cytotoxicity in BPAECs. This study demonstrated the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the protective action of L-type calcium channel blockers against mercury cytotoxicity in vascular ECs, suggesting mechanisms of mercury vasculotoxicity and mercury-induced cardiovascular diseases.
B73. SLEEP DISORDERED BREATHING AND CONTROL OF VENTILATION: BASIC AND TRANSLATIONAL ASPECTS, 2010
ABSTRACT
Toxicological Sciences, 2010
Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As a ... more Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. It is also a major component of cigarette smoke, and its inhalation is associated with decreased pulmonary function, lung cancer, and chronic obstructive pulmonary disease. Ion channels, including the cystic fibrosis transmembrane conductance regulator (CFTR), play a central role in maintaining fluid homeostasis and lung functions. CFTR is mostly expressed in epithelial cells, and little is known about the effect of cadmium exposure on lung epithelial cell function. We show that exposure to cadmium decreases the expression of the CFTR protein and subsequent chloride transport in human airway epithelial cells in vitro. Impairment of CFTR protein expression was also observed in vivo in the lung of mice after intranasal instillation of cadmium. We established that the inhibitory effect of cadmium was not a nonspecific effect of heavy metals, as nickel had no effect on CFTR protein levels. Finally, we show that selected antioxidants, including alpha-tocopherol (vitamin E), but not N-acetylcysteine, can prevent the cadmiuminduced suppression of CFTR. In summary, we have identified cadmium as a regulator of the CFTR chloride channel present in lung epithelial cells. Future strategies to prevent the deleterious effect of cadmium on epithelial cells and lung functions may benefit from the finding that alpha-tocopherol protects CFTR expression and function.
Molecular and Cellular Biochemistry, 2010
Vascular endothelium is vulnerable to the attack of glucose-derived oxoaldehydes (glyoxal and met... more Vascular endothelium is vulnerable to the attack of glucose-derived oxoaldehydes (glyoxal and methylglyoxal) during diabetes, through the formation of advanced glycation end products (AGEs). Although aminoguanidine (AG) has been shown to protect against the AGE-induced adverse effects, its protection against the glyoxal-induced alterations in vascular endothelial cells (ECs) such as cytotoxicity, barrier dysfunction, and inhibition of angiogenesis has not been reported and we investigated this in the bovine pulmonary artery ECs (BPAECs). The results showed that glyoxal (1-10 mM) significantly induced cytotoxicity and mitochondrial dysfunction in a dose-and time-dependent (4-12 h) fashion in ECs. Glyoxal was also observed to significantly inhibit EC proliferation. The study also revealed that glyoxal induced EC barrier dysfunction (loss of trans-endothelial electrical resistance), actin cytoskeletal rearrangement, and tight junction alterations in BPAECs. Furthermore, the results revealed that glyoxal significantly inhibited in vitro angiogenesis on the Matrigel. For the first time, this study demonstrated that AG significantly protected against the glyoxal-induced cytotoxicity, barrier dysfunction, cytoskeletal rearrangement, and inhibition of angiogenesis in BPAECs. Therefore, AG appears as a promising protective agent in the treatment of AGE-induced vascular endothelial alterations and dysfunction during diabetes, presumably by blocking the reactivity of the sugar-derived dicarbonyls such as glyoxal and preventing the formation of AGEs.