Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shoc... more Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shock. The mechanisms responsible for myocardial dysfunction in sepsis remain undefined. S100A1 a member...
Background: S100A1, a Ca2+-sensor protein, is expressed in myocardium and endothelial cells and r... more Background: S100A1, a Ca2+-sensor protein, is expressed in myocardium and endothelial cells and regulates cardiac muscle contractility. Previously, we demonstrated that under basal conditions in vivo, S100A1 knockout mice (KO) exhibited a significant elevation in right ventricular systolic pressure (RVSP), accompanied by an increase in RV hypertrophy. Since RV dysfunction occurs with progression of pulmonary arterial hypertension (PAH), we aimed to determine the impact of deleting S100A1 on progression of PAH in the Sugen-hypoxia (SUHx) model in mice. Methods and Results: C57BL6 (WT) and S100A1 KO mice (n=10 per group) were injected once weekly subcutaneously with SU (20mg/kg) and exposed to chronic Hx (10% O2) for 3 weeks. PAH was assessed by hemodynamic parameters, RV morphology and echocardiography. RV and lung tissue were collected for molecular analysis. In WT and S100A1 KO mice exposed to SUHx, RVSP was similar 31.0±1.90 vs.31.4±2.08, respectively. In RV and lung tissue of WT mice, S100A1 mRNA and p...
Arteriosclerosis, Thrombosis, and Vascular Biology, May 1, 2014
Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease ... more Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease process. Localized hypoxic-induced aortic smooth muscle cell (SMC) apoptosis, a factor amenable to medical intervention, has been reported to participate in the pathogenesis of ascending aortic aneurysm formation (ASAA. β-adrenergic blockers are the drugs most commonly used in the treatment of ASAA. The aim of this study was to investigate the effects of the new third-generation β-blocker nebivolol (NB) on hypoxic-induced smooth muscle cell apoptosis and to characterize the mechanisms activated in this NB action. Treatment of cultured rat thoracic aortic SMC, with NB (10 μM) compared to diluent (100 μM Ascorbic acid) (AA) for 1 hr attenuated hypoxic (5%C02/95%N2) apoptosis as measured by decreases in TUNEL positive staining (15.3+2.3 (AA) vs 5.6+1.2 (NB) % apoptotic nuclei, p<0.05), caspase-3 activity (91.3+2.4 (AA) vs 72.1+0.8 (NB) μmol/mL, p<0.05), the apoptotic ratio of bax/bcl-2 mRNA expression (1.37+0.14 (AA) vs 0.82+0.11 (NB) fold-change, p<0.05), pro-apoptotic miR1 (2.9+0.35 (AA) vs 1.18+0.22 (NB) fold change, p<0.05), and increased anti-apoptotic miR133A (0.74+0.17 (AA) vs 2.3+0.42 (NB) fold change, p<0.05), n=8-10/group. The NB-induced decrease in hypoxic SMC apoptosis was associated with a 5.5 fold increase in nitric oxide (NO) production as quantified by the ratio of Nitrate/Nitrite, a 2.5-3.2 fold increase in Hsp70 mRNA and protein as measured by RT-PCR and Western analysis respectively, and an attenuation of p53 phosphorylation. Blockade of NO production by L-NAME, or siRNA HSP70 knock down, resulted in an increase in p53 phosphorylation and prevented the NB-induced antiapoptotic response of hypoxic SMC. The beneficial pro-survival response of NB in hypoxic thoracic aortic SMCs makes this novel β-blocker clinically relevant in the treatment of ASAA.
The role of the sympathetic nervous system and adrenal medulla in the development of cardiovascul... more The role of the sympathetic nervous system and adrenal medulla in the development of cardiovascular changes and hypertension was studied in spontaneously hypertensive rats (SHRs), and the results compared with age-matched normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was initiated in newborn rats through daily injection with antiserum to nerve growth factor for 1 week, followed by daily injection with guanethidine for 3 weeks. Removal of the adrenal medulla was carried out in 4-week-old rats after the last guanethidine injection. Such a combination treatment was effective in permanently preventing the development of hypertension in the SHRs, and the blood pressure was maintained at the level of WKY rats. The heart rate of the SHRs and WKY rats was not affected by such treatment. Hypertrophy of the heart and of the vessel wall in the mesenteric arteries was also prevented by such treatment. We conclude that in the SHR, the sympathetic nervous system and the adrenal medulla are essential for the development of cardiovascular changes and hypertension.
Introduction: Regular physical activity is considered a cornerstone of cardiovascular disease pre... more Introduction: Regular physical activity is considered a cornerstone of cardiovascular disease prevention and is therefore strongly encouraged by most medical societies. Apart from its beneficial effects on classical cardiovascular risk factors, an anti-inflammatory effect is strongly implicated based on results from observational studies. Hypothesis: Data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a physical activity intervention on the inflammatory marker S100A8/A9, the soluble form of the receptors for advanced glycation end products (sRAGE) and the anioxidant DJ-1. Methods: 332 young army recruits volunteered and 169 completed the study. The participants underwent the standard basic training of Greek army recruits which includes 2 hours of aerobic exercise, 5 times a week. Plasma S100A8/A9, sRAGE and DJ-1 were measured at the beginning and at the end of the training period. Results: At the end of the training period we observed a statistically significant reduction of S100A8/A9 (630.98 vs 472.12 ng/ml, p=0.001) and soluble RAGE (416.21 vs 225.19 pg/ml, p=0.001) while DJ-1 was significantly increased (62.48 vs 74.45 ng/ml, p<0.05). S100A8/A9 reduction was positively correlated with body weight (r=.238 [.106, .375], p=0.002), indicating that heavier individuals could benefit more from an exercise intervention. Conclusions: A 4 weeks military exercise training intervention resulted in a reduction of the pro-inflammatory S100A8/A9 complex as well as an increase of the anti-oxidant DJ- 1 protein, supporting the anti-inflammatory and anti-oxidant effects of physical activity. The observed reduction of sRAGEs was interpreted as a sign of diminished AGE-RAGE axis activation.
Introduction: Cardiac overexpression of S100A6, a member of the family of EF-hand calcium binding... more Introduction: Cardiac overexpression of S100A6, a member of the family of EF-hand calcium binding proteins attenuates left ventricular remodeling and preserves cardiac function after myocardial inf...
Although marrow-derived MSCs may be beneficial in treating models of ischemic heart disease, thei... more Although marrow-derived MSCs may be beneficial in treating models of ischemic heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. MSCs from female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific α-myosin heavy chain promoter were co-cultured with male rat embryonic cardiomyocytes (rCMs). This novel in vitro model permits identification and functional analysis of putatively transdifferentiated MSCs based on GFP expression. In co-culture, 6.3% of MSCs became GFP+. Quantitative PCR using murine-specific primers revealed that co-cultured MSCs express the cardiac-specific genes atrial natriuretic factor, Nkx2.5 and α-cardiac actin. Furthermore, immunohistochemistry on GFP+ MSCs established co-expression of the sarcomeric proteins troponin I and α-actinin, but without a clear sarcomeric pattern. Despite expression of cardiac genes, patch-clamp experiments illustrate that GFP+ MSCs did not fire action potentials and did not express voltage gated sodium and calcium currents (INa and ICa). In contrast, action potentials, INa and ICa were readily observed in all GFP− rCMs studied in the co-cultures. When investigated using slow voltage ramps, GFP+ MSCs displayed electrical properties typical of non-excitable cells, suggesting retention of a stromal cell phenotype. Indeed, detailed immunophenotyping of GFP+ MSCs demonstrated expression of all antigens used to characterize MSCs as well as the acquisition of additional markers of cardiomyocytes with the phenotype: CD45− CD34+ CD73+ CD105+ CD90+ CD44+ SDF1+ CD134L+ collagen type IV+ vimentin+ troponin T+ troponin I+ a-actinin+ connexin 43+. Although cell fusion between rCMs and MSCs was detectable by fluorescence in situ hybridization, the very low frequency (0.68%) cannot account for the phenotype of the GFP+ MSCs. In conclusion, we have identified a MSC population that shows plasticity towards the cardiomyocyte lineage but that retains mesenchymal stromal cell properties, including a non-excitable electrophysiological phenotype. The demonstration of a MSC-derived population co-expressing cardiac and stromal cell markers may explain the conflicting results in the literature regarding transdifferentiation and indicates the importance of extensive immunophenotypic and functional analysis of the manipulated cells. The data also infer the need to identify mechanisms other than cardiomyocyte differentiation that underlie the effects of MSCs on myocardial injury.
The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal st... more The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal stromal cells (BM-MSCs) to differentiate into cardiomyocytes have been questioned due to the transient presence of donor cells at injury site following myocardial infarction (MI) suggesting that the MSC-induced improvement in hemodynamic function may be attributable to paracrine effects. We showed that S100A6, a 20 kDa EF-hand calcium-binding dimer, is upregulated and secreted following MI and forced expression post-MI was beneficial to the preservation of cardiac function. The aim of this study was to determine whether the beneficial effects of infused BM-MSCs may be related to the autocrine secretion of S100A6. Balb/c murine cultured green fluorescence protein (GFP)-marked BM-MSCs express S100A6 at baseline and in response to hypoxia (5%C02/95% N2) for 1 hr increase S100A6 mRNA and protein (2-3 fold, and release S100A6 (1 nM) in the culture media, responses inhibited in BM-MSCs transfected with S100A6 siRNA. Treatment of neonatal Balb/c cardiac myocytes with human recombinant S100A6 (1nM) for 1-24 hrs attenuated baseline apoptosis (30 per cent decrease in BAX/BCL2 ratio), induced cyclin-dependent kinase 1(CDK1) mRNA 1.5 fold, miR199a 2 fold and myocyte proliferation 2.5 fold, the latter inhibited by anti-miR 199a. In 12 week old Balb/c mice, saline or GFP-marked BM-MSCs transfected with either a scrambled or S100A6 siRNA were infused intravenously 3-4 hrs post coronary artery ligation. After 3-4 days the GFP-marked cells were confined to ischemic areas and represented approximately 10% of total cellularity and co-expressed collagen type IV and myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Despite the absence of donor cells in the infarcted myocardium 21 days after infusion, mice that have received MSCs alone compared to MSCs transfected with an S100A6 siRNA or saline alone showed a 6-fold increase in S100A6 mRNA and protein, 3-fold increase in miR199a in peri-infarcted myocardium, attenuated myocyte hypertrophy, decreased fibrosis and apoptosis, and preservation of cardiac function. In conclusion, the secretion of S100A6 by infused BM-MSCs may contribute in limiting adverse LV remodeling post-MI.
Journal of Cardiovascular Pharmacology, Jun 1, 1998
Arterial hypertrophy in response to hypertension includes increases in the connective tissue prot... more Arterial hypertrophy in response to hypertension includes increases in the connective tissue proteins elastin and collagen. Regression of arterial hypertrophy depends not only on blood pressure normalization but also on the specific antihypertensive treatment. Consequently, each drug class may exert an influence on connective tissue proteins. We evaluated the arterial connective tissue response of 16-week-old spontaneously hypertensive rats (SHRs) to treatment with minoxidil, 120 mg/L, drinking water for 10 weeks. Despite a decrease in blood pressure, minoxidil had no effect on arterial weight or collagen content but increased elastin content in the abdominal aorta, renal, and superior mesenteric arteries. The increase in elastin content in the abdominal aorta and superior mesenteric artery was accompanied by a decrease in tissue elastase activity. Thus the minoxidil-induced increase in arterial elastin content may be related to a direct effect of the drug to decrease elastase activity in these tissues.
S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the r... more S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of β myosin heavy chain (MHC), skeletal α actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor α. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyte-restricted (αMHC) expression of tTA (αMHC-tTA). We compared S100A6-αMHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-α-MHC-tTA mice off DOX compared with S100A6-α-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-α-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.
Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shoc... more Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shock. The mechanisms responsible for myocardial dysfunction in sepsis remain undefined. S100A1 a member...
Background: S100A1, a Ca2+-sensor protein, is expressed in myocardium and endothelial cells and r... more Background: S100A1, a Ca2+-sensor protein, is expressed in myocardium and endothelial cells and regulates cardiac muscle contractility. Previously, we demonstrated that under basal conditions in vivo, S100A1 knockout mice (KO) exhibited a significant elevation in right ventricular systolic pressure (RVSP), accompanied by an increase in RV hypertrophy. Since RV dysfunction occurs with progression of pulmonary arterial hypertension (PAH), we aimed to determine the impact of deleting S100A1 on progression of PAH in the Sugen-hypoxia (SUHx) model in mice. Methods and Results: C57BL6 (WT) and S100A1 KO mice (n=10 per group) were injected once weekly subcutaneously with SU (20mg/kg) and exposed to chronic Hx (10% O2) for 3 weeks. PAH was assessed by hemodynamic parameters, RV morphology and echocardiography. RV and lung tissue were collected for molecular analysis. In WT and S100A1 KO mice exposed to SUHx, RVSP was similar 31.0±1.90 vs.31.4±2.08, respectively. In RV and lung tissue of WT mice, S100A1 mRNA and p...
Arteriosclerosis, Thrombosis, and Vascular Biology, May 1, 2014
Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease ... more Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease process. Localized hypoxic-induced aortic smooth muscle cell (SMC) apoptosis, a factor amenable to medical intervention, has been reported to participate in the pathogenesis of ascending aortic aneurysm formation (ASAA. β-adrenergic blockers are the drugs most commonly used in the treatment of ASAA. The aim of this study was to investigate the effects of the new third-generation β-blocker nebivolol (NB) on hypoxic-induced smooth muscle cell apoptosis and to characterize the mechanisms activated in this NB action. Treatment of cultured rat thoracic aortic SMC, with NB (10 μM) compared to diluent (100 μM Ascorbic acid) (AA) for 1 hr attenuated hypoxic (5%C02/95%N2) apoptosis as measured by decreases in TUNEL positive staining (15.3+2.3 (AA) vs 5.6+1.2 (NB) % apoptotic nuclei, p<0.05), caspase-3 activity (91.3+2.4 (AA) vs 72.1+0.8 (NB) μmol/mL, p<0.05), the apoptotic ratio of bax/bcl-2 mRNA expression (1.37+0.14 (AA) vs 0.82+0.11 (NB) fold-change, p<0.05), pro-apoptotic miR1 (2.9+0.35 (AA) vs 1.18+0.22 (NB) fold change, p<0.05), and increased anti-apoptotic miR133A (0.74+0.17 (AA) vs 2.3+0.42 (NB) fold change, p<0.05), n=8-10/group. The NB-induced decrease in hypoxic SMC apoptosis was associated with a 5.5 fold increase in nitric oxide (NO) production as quantified by the ratio of Nitrate/Nitrite, a 2.5-3.2 fold increase in Hsp70 mRNA and protein as measured by RT-PCR and Western analysis respectively, and an attenuation of p53 phosphorylation. Blockade of NO production by L-NAME, or siRNA HSP70 knock down, resulted in an increase in p53 phosphorylation and prevented the NB-induced antiapoptotic response of hypoxic SMC. The beneficial pro-survival response of NB in hypoxic thoracic aortic SMCs makes this novel β-blocker clinically relevant in the treatment of ASAA.
The role of the sympathetic nervous system and adrenal medulla in the development of cardiovascul... more The role of the sympathetic nervous system and adrenal medulla in the development of cardiovascular changes and hypertension was studied in spontaneously hypertensive rats (SHRs), and the results compared with age-matched normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was initiated in newborn rats through daily injection with antiserum to nerve growth factor for 1 week, followed by daily injection with guanethidine for 3 weeks. Removal of the adrenal medulla was carried out in 4-week-old rats after the last guanethidine injection. Such a combination treatment was effective in permanently preventing the development of hypertension in the SHRs, and the blood pressure was maintained at the level of WKY rats. The heart rate of the SHRs and WKY rats was not affected by such treatment. Hypertrophy of the heart and of the vessel wall in the mesenteric arteries was also prevented by such treatment. We conclude that in the SHR, the sympathetic nervous system and the adrenal medulla are essential for the development of cardiovascular changes and hypertension.
Introduction: Regular physical activity is considered a cornerstone of cardiovascular disease pre... more Introduction: Regular physical activity is considered a cornerstone of cardiovascular disease prevention and is therefore strongly encouraged by most medical societies. Apart from its beneficial effects on classical cardiovascular risk factors, an anti-inflammatory effect is strongly implicated based on results from observational studies. Hypothesis: Data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a physical activity intervention on the inflammatory marker S100A8/A9, the soluble form of the receptors for advanced glycation end products (sRAGE) and the anioxidant DJ-1. Methods: 332 young army recruits volunteered and 169 completed the study. The participants underwent the standard basic training of Greek army recruits which includes 2 hours of aerobic exercise, 5 times a week. Plasma S100A8/A9, sRAGE and DJ-1 were measured at the beginning and at the end of the training period. Results: At the end of the training period we observed a statistically significant reduction of S100A8/A9 (630.98 vs 472.12 ng/ml, p=0.001) and soluble RAGE (416.21 vs 225.19 pg/ml, p=0.001) while DJ-1 was significantly increased (62.48 vs 74.45 ng/ml, p<0.05). S100A8/A9 reduction was positively correlated with body weight (r=.238 [.106, .375], p=0.002), indicating that heavier individuals could benefit more from an exercise intervention. Conclusions: A 4 weeks military exercise training intervention resulted in a reduction of the pro-inflammatory S100A8/A9 complex as well as an increase of the anti-oxidant DJ- 1 protein, supporting the anti-inflammatory and anti-oxidant effects of physical activity. The observed reduction of sRAGEs was interpreted as a sign of diminished AGE-RAGE axis activation.
Introduction: Cardiac overexpression of S100A6, a member of the family of EF-hand calcium binding... more Introduction: Cardiac overexpression of S100A6, a member of the family of EF-hand calcium binding proteins attenuates left ventricular remodeling and preserves cardiac function after myocardial inf...
Although marrow-derived MSCs may be beneficial in treating models of ischemic heart disease, thei... more Although marrow-derived MSCs may be beneficial in treating models of ischemic heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. MSCs from female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific α-myosin heavy chain promoter were co-cultured with male rat embryonic cardiomyocytes (rCMs). This novel in vitro model permits identification and functional analysis of putatively transdifferentiated MSCs based on GFP expression. In co-culture, 6.3% of MSCs became GFP+. Quantitative PCR using murine-specific primers revealed that co-cultured MSCs express the cardiac-specific genes atrial natriuretic factor, Nkx2.5 and α-cardiac actin. Furthermore, immunohistochemistry on GFP+ MSCs established co-expression of the sarcomeric proteins troponin I and α-actinin, but without a clear sarcomeric pattern. Despite expression of cardiac genes, patch-clamp experiments illustrate that GFP+ MSCs did not fire action potentials and did not express voltage gated sodium and calcium currents (INa and ICa). In contrast, action potentials, INa and ICa were readily observed in all GFP− rCMs studied in the co-cultures. When investigated using slow voltage ramps, GFP+ MSCs displayed electrical properties typical of non-excitable cells, suggesting retention of a stromal cell phenotype. Indeed, detailed immunophenotyping of GFP+ MSCs demonstrated expression of all antigens used to characterize MSCs as well as the acquisition of additional markers of cardiomyocytes with the phenotype: CD45− CD34+ CD73+ CD105+ CD90+ CD44+ SDF1+ CD134L+ collagen type IV+ vimentin+ troponin T+ troponin I+ a-actinin+ connexin 43+. Although cell fusion between rCMs and MSCs was detectable by fluorescence in situ hybridization, the very low frequency (0.68%) cannot account for the phenotype of the GFP+ MSCs. In conclusion, we have identified a MSC population that shows plasticity towards the cardiomyocyte lineage but that retains mesenchymal stromal cell properties, including a non-excitable electrophysiological phenotype. The demonstration of a MSC-derived population co-expressing cardiac and stromal cell markers may explain the conflicting results in the literature regarding transdifferentiation and indicates the importance of extensive immunophenotypic and functional analysis of the manipulated cells. The data also infer the need to identify mechanisms other than cardiomyocyte differentiation that underlie the effects of MSCs on myocardial injury.
The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal st... more The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal stromal cells (BM-MSCs) to differentiate into cardiomyocytes have been questioned due to the transient presence of donor cells at injury site following myocardial infarction (MI) suggesting that the MSC-induced improvement in hemodynamic function may be attributable to paracrine effects. We showed that S100A6, a 20 kDa EF-hand calcium-binding dimer, is upregulated and secreted following MI and forced expression post-MI was beneficial to the preservation of cardiac function. The aim of this study was to determine whether the beneficial effects of infused BM-MSCs may be related to the autocrine secretion of S100A6. Balb/c murine cultured green fluorescence protein (GFP)-marked BM-MSCs express S100A6 at baseline and in response to hypoxia (5%C02/95% N2) for 1 hr increase S100A6 mRNA and protein (2-3 fold, and release S100A6 (1 nM) in the culture media, responses inhibited in BM-MSCs transfected with S100A6 siRNA. Treatment of neonatal Balb/c cardiac myocytes with human recombinant S100A6 (1nM) for 1-24 hrs attenuated baseline apoptosis (30 per cent decrease in BAX/BCL2 ratio), induced cyclin-dependent kinase 1(CDK1) mRNA 1.5 fold, miR199a 2 fold and myocyte proliferation 2.5 fold, the latter inhibited by anti-miR 199a. In 12 week old Balb/c mice, saline or GFP-marked BM-MSCs transfected with either a scrambled or S100A6 siRNA were infused intravenously 3-4 hrs post coronary artery ligation. After 3-4 days the GFP-marked cells were confined to ischemic areas and represented approximately 10% of total cellularity and co-expressed collagen type IV and myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Despite the absence of donor cells in the infarcted myocardium 21 days after infusion, mice that have received MSCs alone compared to MSCs transfected with an S100A6 siRNA or saline alone showed a 6-fold increase in S100A6 mRNA and protein, 3-fold increase in miR199a in peri-infarcted myocardium, attenuated myocyte hypertrophy, decreased fibrosis and apoptosis, and preservation of cardiac function. In conclusion, the secretion of S100A6 by infused BM-MSCs may contribute in limiting adverse LV remodeling post-MI.
Journal of Cardiovascular Pharmacology, Jun 1, 1998
Arterial hypertrophy in response to hypertension includes increases in the connective tissue prot... more Arterial hypertrophy in response to hypertension includes increases in the connective tissue proteins elastin and collagen. Regression of arterial hypertrophy depends not only on blood pressure normalization but also on the specific antihypertensive treatment. Consequently, each drug class may exert an influence on connective tissue proteins. We evaluated the arterial connective tissue response of 16-week-old spontaneously hypertensive rats (SHRs) to treatment with minoxidil, 120 mg/L, drinking water for 10 weeks. Despite a decrease in blood pressure, minoxidil had no effect on arterial weight or collagen content but increased elastin content in the abdominal aorta, renal, and superior mesenteric arteries. The increase in elastin content in the abdominal aorta and superior mesenteric artery was accompanied by a decrease in tissue elastase activity. Thus the minoxidil-induced increase in arterial elastin content may be related to a direct effect of the drug to decrease elastase activity in these tissues.
S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the r... more S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of β myosin heavy chain (MHC), skeletal α actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor α. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyte-restricted (αMHC) expression of tTA (αMHC-tTA). We compared S100A6-αMHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-α-MHC-tTA mice off DOX compared with S100A6-α-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-α-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.
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Papers by James Tsoporis