Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl... more Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLe X ) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis.The glycosylation inhibitor, per-O-acetylated GlcNAch1,3Galh-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLe X in tumor cells.To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells. Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectindeficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model. Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLe X -and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLe X in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or sLe X -dependent inflammation. Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycosidebased therapy for the treatment of hematogenous dissemination of tumor cells.
Journal of molecular and cellular cardiology, Jan 9, 2015
Cardiac fibrosis is one of the major components of the healing mechanism following any injury of ... more Cardiac fibrosis is one of the major components of the healing mechanism following any injury of the heart and as such may contribute to both systolic and diastolic dysfunction in a range of pathophysiologic conditions. Canonically, it can occur as part of the remodeling process that occurs following myocardial infarction or that follows as a response to pressure overload. Integrins are cell surface receptors which act in both cellular adhesion and signaling. Most importantly, in the context of the continuously contracting myocardium, they are recognized as mechanotransducers. They have been implicated in the development of fibrosis in several organs, including the heart. This review will focus on the involvement of integrins and integrin-related proteins, in cardiac fibrosis, outlining the roles of these proteins in the fibrotic responses in specific cardiac pathologies, discuss some of the common end effectors (angiotensin II, transforming growth factor beta 1 and mechanical stres...
To study change patterns of 24 h intraocular pressure (IOP) in conscious and freely moving mice u... more To study change patterns of 24 h intraocular pressure (IOP) in conscious and freely moving mice using telemetry. Adult C57BL/6J and CBA/CaJ mice were entrained to a standard 12 h light and 12 h dark cycle. A telemetric pressure transmitter was implanted subcutaneously on the upper back of each light-dark entrained mouse, and the pressure catheter tip was inserted into the vitreous chamber. Broadcasted IOP data were received at 120 Hz. Means of 2 min IOP were recorded every 5 min for 4-13 days to generate the 24 h IOP pattern in each mouse strain. The pattern of IOP in the C57BL/6J strain was also determined under an acute constant dark condition for 24 h. There were distinct patterns of 24 h IOP in the C57BL/6J and CBA/CaJ mouse strains. Under the standard light-dark condition, IOP was higher during the dark period than the light period in both strains. Elevation in IOP from the light period to the dark period was significantly smaller in the CBA/CaJ strain (1.6+/-1.7 mmHg, mean+/- ...
Journal of Ocular Pharmacology and Therapeutics, 2007
The aim of this study was to investigate the resistance to blood flow in the ophthalmic artery of... more The aim of this study was to investigate the resistance to blood flow in the ophthalmic artery of rabbits receiving topical treatment with timolol. Eight (8) New Zealand albino rabbits received 20 mul of timolol treatment (vehicle, 0.1%, 0.33%, 1%, and 3.3%) on the right eye. Blood-flow velocity in the ophthalmic artery was determined in the treated eye using color Doppler imaging (CDI) with a 12-MHz linear ultrasound transducer prior to the treatment and at 0.5, 1, 1.5, 2, and 3 h after the treatment. Intraocular pressure (IOP) was measured in both eyes, using a pneumatonometer at the same time points. Pourcelot's resistive index of blood flow was calculated, using the peak systolic velocity and the end diastolic velocity. A control experiment was performed with CDI obtained from the right eye when the left eye was treated with 1% timolol. In the eye treated with 1% and 3.3% timolol, a dose-dependent increase in the resistive index of blood flow occurred in the ophthalmic artery. No change in the resistive index occurred when the contralateral eye was treated with 1% timolol. Changes of IOP were not different between the two eyes under all the experimental conditions. Timolol, at all concentrations, caused a significant reduction of heart rate. A similar reduction of heart rate occurred when either eye was treated with 1% timolol. Topical treatment with timolol in rabbits can increase the resistance to blood flow in the ophthalmic artery. This effect is caused by a mechanism local to the eye and is not dependent on an IOP change.
Journal of Ocular Pharmacology and Therapeutics, 2007
The aim of this study was to investigate sympathetic influences on blood-flow velocity and resist... more The aim of this study was to investigate sympathetic influences on blood-flow velocity and resistance in the rabbit ophthalmic artery during the transition period from the light to the dark phase. Eight (8) New Zealand albino rabbits were entrained to a daily 12-h light and 12-h dark cycle. Blood-flow velocities in the ophthalmic artery were determined at -2 (baseline), 0, 2, and 4 h after the onset of darkness. Pulsed and color Doppler images of the ophthalmic artery were recorded using a 12-MHz linear ultrasound transducer. Resistive index of blood flow was calculated using the peak systolic velocity and the end diastolic velocity. Measurements of intraocular pressure (IOP) were taken, using a pneumatonometer at the same time points. Blood-flow velocity, resistive index, and IOP were also determined in the same rabbits after surgical decentralization of the ocular sympathetic nerves. Compared with the baseline at -2 h, a significant increase in the resistive index of blood flow in the ophthalmic artery occurred at 2 and 4 h after the onset of darkness. Parallel elevations of IOP were observed. After the sympathetic decentralization, peak systolic and end diastolic velocities decreased and resistive indexes increased from the presurgical values in the ophthalmic artery. In the postsurgical rabbits, elevation of IOP was absent during the light-dark transition period. There was also no time-dependent increase of resistive index in the ophthalmic artery. During the light-dark transition period, resistance to blood flow in the rabbit ophthalmic artery increases in parallel to IOP elevation. The removal of sympathetic activities decreases blood-flow velocity, but increases blood-flow resistance. Like the endogenous elevation of IOP, the time-dependent increase of resistance to blood flow in the rabbit ophthalmic artery during the light-dark transition period depends upon, at least partially, ocular sympathetic activities.
Talin is an integrin-actin linker essential for integrin activation. Results: Talin1 has distinct... more Talin is an integrin-actin linker essential for integrin activation. Results: Talin1 has distinct developmental and postnatal expression in heart versus Talin2. Cardiac-myocyte specific Talin1 deletion alters physiological and molecular responses of the myocardium to stress. Conclusion: Talin1 has a unique mechanotransductive role in the cardiomyocyte. Significance: Reduction of talin1 in cardiomyocytes may have beneficial effects in the stressed myocardium.
Sprague-Dawley rats 10-12 weeks of age were entrained to a standard light-dark cycle with lights ... more Sprague-Dawley rats 10-12 weeks of age were entrained to a standard light-dark cycle with lights turned on at 6 am and off at 6 pm. Variations of 24-hour aqueous humor protein concentration were determined. Samples were taken every 4 hours (N = 10-14) under the standard light-dark condition at 8 pm, midnight, 4 am, 8 am, noon, and 4 pm. Under an acute constant dark condition, when lights were not turned on at 6 am, samples were collected at 8 am, noon, 4 pm, and 8 pm. Aqueous humor protein concentrations under the standard light-dark condition were found in the range of 0.305 ± 0.115 mg/ml (mean ± SD, N = 10) at midnight to 1.505 ± 0.342 mg/ml (N = 14) at noon. The 3 lightphase protein concentrations were each higher than the 3 dark-phase concentrations. Aqueous humor protein concentrations at 8 am, noon, and 4 pm under the acute constant dark condition were each higher than the concentrations at 8 pm (after both 2 hours and 26 hours in the dark), midnight, and 4 am, demonstrating an endogenously driven 24-hour pattern. At 8 am, noon, and 4 pm, protein concentrations were 56-147% higher when exposed to light. Intraocular pressure (IOP) was monitored using telemetry in separate groups of light-dark entrained rats under the standard lightdark condition and the acute constant dark condition. The 24-hour IOP pattern was inverse to the 24hour pattern of aqueous humor protein concentration under the standard light-dark condition, and this IOP pattern was not altered by the acute constant dark condition. In conclusion, an endogenously driven 24-hour variation of aqueous humor protein concentration occurred in Sprague-Dawley rats with higher concentrations during the light-phase than the dark-phase. This endogenous pattern of protein concentration was accentuated by a direct effect of light, which was unrelated to the 24-hour pattern of IOP.
How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study... more How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which 1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of 1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrinlinked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte 1 integrin expression modified adrenergic-mediated signaling through extracellular signal-regulated kinase, p38, and Akt. Reduction of 1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that 1 integrin expression is required for proper mechanotransductive and adrener-gic responses of the adult heart. (Am J Pathol 2012, 180: 952-962; DOI: 10.1016/j.ajpath.2011.12.007)
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015
β1 integrins (β1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Gi... more β1 integrins (β1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Given their close localization, as well as their role in mechanotransduction and signaling, we hypothesized that caveolin (Cav) proteins might regulate integrins in the CM. β1 localization, complex formation, activation state, and signaling were analyzed using wild-type, Cav3 knockout, and Cav3 CM-specific transgenic heart and myocyte samples. Studies were performed under basal and mechanically loaded conditions. We found that: 1) β1 and Cav3 colocalize in CM and coimmunoprecipitate from CM protein lysates; 2) β1 is detected in a subset of caveolae; 3) loss of Cav3 caused reduction of β1D integrin isoform and active β1 integrin from the buoyant domains in the heart; 4) increased expression of myocyte Cav3 correlates with increased active β1 integrin in adult CM; 5) in vivo pressure overload of the wild-type heart results in increased activated integrin in buoyant membrane domains along wit...
Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl... more Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLe X ) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis.The glycosylation inhibitor, per-O-acetylated GlcNAch1,3Galh-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLe X in tumor cells.To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells. Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectindeficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model. Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLe X -and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLe X in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or sLe X -dependent inflammation. Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycosidebased therapy for the treatment of hematogenous dissemination of tumor cells.
Journal of molecular and cellular cardiology, Jan 9, 2015
Cardiac fibrosis is one of the major components of the healing mechanism following any injury of ... more Cardiac fibrosis is one of the major components of the healing mechanism following any injury of the heart and as such may contribute to both systolic and diastolic dysfunction in a range of pathophysiologic conditions. Canonically, it can occur as part of the remodeling process that occurs following myocardial infarction or that follows as a response to pressure overload. Integrins are cell surface receptors which act in both cellular adhesion and signaling. Most importantly, in the context of the continuously contracting myocardium, they are recognized as mechanotransducers. They have been implicated in the development of fibrosis in several organs, including the heart. This review will focus on the involvement of integrins and integrin-related proteins, in cardiac fibrosis, outlining the roles of these proteins in the fibrotic responses in specific cardiac pathologies, discuss some of the common end effectors (angiotensin II, transforming growth factor beta 1 and mechanical stres...
To study change patterns of 24 h intraocular pressure (IOP) in conscious and freely moving mice u... more To study change patterns of 24 h intraocular pressure (IOP) in conscious and freely moving mice using telemetry. Adult C57BL/6J and CBA/CaJ mice were entrained to a standard 12 h light and 12 h dark cycle. A telemetric pressure transmitter was implanted subcutaneously on the upper back of each light-dark entrained mouse, and the pressure catheter tip was inserted into the vitreous chamber. Broadcasted IOP data were received at 120 Hz. Means of 2 min IOP were recorded every 5 min for 4-13 days to generate the 24 h IOP pattern in each mouse strain. The pattern of IOP in the C57BL/6J strain was also determined under an acute constant dark condition for 24 h. There were distinct patterns of 24 h IOP in the C57BL/6J and CBA/CaJ mouse strains. Under the standard light-dark condition, IOP was higher during the dark period than the light period in both strains. Elevation in IOP from the light period to the dark period was significantly smaller in the CBA/CaJ strain (1.6+/-1.7 mmHg, mean+/- ...
Journal of Ocular Pharmacology and Therapeutics, 2007
The aim of this study was to investigate the resistance to blood flow in the ophthalmic artery of... more The aim of this study was to investigate the resistance to blood flow in the ophthalmic artery of rabbits receiving topical treatment with timolol. Eight (8) New Zealand albino rabbits received 20 mul of timolol treatment (vehicle, 0.1%, 0.33%, 1%, and 3.3%) on the right eye. Blood-flow velocity in the ophthalmic artery was determined in the treated eye using color Doppler imaging (CDI) with a 12-MHz linear ultrasound transducer prior to the treatment and at 0.5, 1, 1.5, 2, and 3 h after the treatment. Intraocular pressure (IOP) was measured in both eyes, using a pneumatonometer at the same time points. Pourcelot's resistive index of blood flow was calculated, using the peak systolic velocity and the end diastolic velocity. A control experiment was performed with CDI obtained from the right eye when the left eye was treated with 1% timolol. In the eye treated with 1% and 3.3% timolol, a dose-dependent increase in the resistive index of blood flow occurred in the ophthalmic artery. No change in the resistive index occurred when the contralateral eye was treated with 1% timolol. Changes of IOP were not different between the two eyes under all the experimental conditions. Timolol, at all concentrations, caused a significant reduction of heart rate. A similar reduction of heart rate occurred when either eye was treated with 1% timolol. Topical treatment with timolol in rabbits can increase the resistance to blood flow in the ophthalmic artery. This effect is caused by a mechanism local to the eye and is not dependent on an IOP change.
Journal of Ocular Pharmacology and Therapeutics, 2007
The aim of this study was to investigate sympathetic influences on blood-flow velocity and resist... more The aim of this study was to investigate sympathetic influences on blood-flow velocity and resistance in the rabbit ophthalmic artery during the transition period from the light to the dark phase. Eight (8) New Zealand albino rabbits were entrained to a daily 12-h light and 12-h dark cycle. Blood-flow velocities in the ophthalmic artery were determined at -2 (baseline), 0, 2, and 4 h after the onset of darkness. Pulsed and color Doppler images of the ophthalmic artery were recorded using a 12-MHz linear ultrasound transducer. Resistive index of blood flow was calculated using the peak systolic velocity and the end diastolic velocity. Measurements of intraocular pressure (IOP) were taken, using a pneumatonometer at the same time points. Blood-flow velocity, resistive index, and IOP were also determined in the same rabbits after surgical decentralization of the ocular sympathetic nerves. Compared with the baseline at -2 h, a significant increase in the resistive index of blood flow in the ophthalmic artery occurred at 2 and 4 h after the onset of darkness. Parallel elevations of IOP were observed. After the sympathetic decentralization, peak systolic and end diastolic velocities decreased and resistive indexes increased from the presurgical values in the ophthalmic artery. In the postsurgical rabbits, elevation of IOP was absent during the light-dark transition period. There was also no time-dependent increase of resistive index in the ophthalmic artery. During the light-dark transition period, resistance to blood flow in the rabbit ophthalmic artery increases in parallel to IOP elevation. The removal of sympathetic activities decreases blood-flow velocity, but increases blood-flow resistance. Like the endogenous elevation of IOP, the time-dependent increase of resistance to blood flow in the rabbit ophthalmic artery during the light-dark transition period depends upon, at least partially, ocular sympathetic activities.
Talin is an integrin-actin linker essential for integrin activation. Results: Talin1 has distinct... more Talin is an integrin-actin linker essential for integrin activation. Results: Talin1 has distinct developmental and postnatal expression in heart versus Talin2. Cardiac-myocyte specific Talin1 deletion alters physiological and molecular responses of the myocardium to stress. Conclusion: Talin1 has a unique mechanotransductive role in the cardiomyocyte. Significance: Reduction of talin1 in cardiomyocytes may have beneficial effects in the stressed myocardium.
Sprague-Dawley rats 10-12 weeks of age were entrained to a standard light-dark cycle with lights ... more Sprague-Dawley rats 10-12 weeks of age were entrained to a standard light-dark cycle with lights turned on at 6 am and off at 6 pm. Variations of 24-hour aqueous humor protein concentration were determined. Samples were taken every 4 hours (N = 10-14) under the standard light-dark condition at 8 pm, midnight, 4 am, 8 am, noon, and 4 pm. Under an acute constant dark condition, when lights were not turned on at 6 am, samples were collected at 8 am, noon, 4 pm, and 8 pm. Aqueous humor protein concentrations under the standard light-dark condition were found in the range of 0.305 ± 0.115 mg/ml (mean ± SD, N = 10) at midnight to 1.505 ± 0.342 mg/ml (N = 14) at noon. The 3 lightphase protein concentrations were each higher than the 3 dark-phase concentrations. Aqueous humor protein concentrations at 8 am, noon, and 4 pm under the acute constant dark condition were each higher than the concentrations at 8 pm (after both 2 hours and 26 hours in the dark), midnight, and 4 am, demonstrating an endogenously driven 24-hour pattern. At 8 am, noon, and 4 pm, protein concentrations were 56-147% higher when exposed to light. Intraocular pressure (IOP) was monitored using telemetry in separate groups of light-dark entrained rats under the standard lightdark condition and the acute constant dark condition. The 24-hour IOP pattern was inverse to the 24hour pattern of aqueous humor protein concentration under the standard light-dark condition, and this IOP pattern was not altered by the acute constant dark condition. In conclusion, an endogenously driven 24-hour variation of aqueous humor protein concentration occurred in Sprague-Dawley rats with higher concentrations during the light-phase than the dark-phase. This endogenous pattern of protein concentration was accentuated by a direct effect of light, which was unrelated to the 24-hour pattern of IOP.
How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study... more How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which 1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of 1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrinlinked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte 1 integrin expression modified adrenergic-mediated signaling through extracellular signal-regulated kinase, p38, and Akt. Reduction of 1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that 1 integrin expression is required for proper mechanotransductive and adrener-gic responses of the adult heart. (Am J Pathol 2012, 180: 952-962; DOI: 10.1016/j.ajpath.2011.12.007)
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015
β1 integrins (β1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Gi... more β1 integrins (β1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Given their close localization, as well as their role in mechanotransduction and signaling, we hypothesized that caveolin (Cav) proteins might regulate integrins in the CM. β1 localization, complex formation, activation state, and signaling were analyzed using wild-type, Cav3 knockout, and Cav3 CM-specific transgenic heart and myocyte samples. Studies were performed under basal and mechanically loaded conditions. We found that: 1) β1 and Cav3 colocalize in CM and coimmunoprecipitate from CM protein lysates; 2) β1 is detected in a subset of caveolae; 3) loss of Cav3 caused reduction of β1D integrin isoform and active β1 integrin from the buoyant domains in the heart; 4) increased expression of myocyte Cav3 correlates with increased active β1 integrin in adult CM; 5) in vivo pressure overload of the wild-type heart results in increased activated integrin in buoyant membrane domains along wit...
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