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Thyroid hormone attenuates cardiac remodeling and improves haemodynamics early after myocardial infarction
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
The aim of the study has been to research the activation of the ET-1 system, ECE, ETA and ETB in ischemic(ICM) and dilated (DCM) end-stage heart failure. The tissue for the study was harvested during a transplantation procedure. Samples from cardiologically healthy donors were taken as control. The study of RNA expression for ET-1 and its converting enzyme with the quantitative RT-PCR method was performed. Protein levels of ET-1, ETA and ETB were measured with the Western Blotting. Results: Both mRNA expression and protein level of ET-1 in l LV from nonfailing donors (NF) and from patients with HF due to ICM were comparable, whereas in those with DCM were higher. The mRNA level for ECE was higher in both ICM and DCM patients. In LV in both groups studied, an elevated level of ETA receptors was found. In DCM, The ETA level was particularly high in patients 35 and 36, who had enlarged LV and large fibrosis. We measured expression of ERK1/2 and p38 kinases. In the case of ERK1/2 no significant differences in activity were found between the patient groups and the controls. Only DCM patients were found to develop an activation of a pathway via p38. Basing on the obtained results we can suppose that the regulation of the endothelin system in the failed heart muscle does not occur only at the RNA level of the gene encoding ET-1 but it occurs at the ECE and ETA levels as well. The fact that p-38 is activated only in DCM proves that ischemic and dilated cardiomyopathies are different pathological entities. Keywords: Heart failure; Gene expression; ET-1 system doi:10.1016/j.yjmcc.2007.03.478
Follistatin gene expression is elevated in heart failure and decreases following recovery E. Lara-Pezzi, L.E. Felkin, E. Birks, M.H. Yacoub, N. Rosenthal, P.J. Barton. Harefield Heart Science Centre, Imperial College London, UK The molecular mechanisms underlying heart failure (HF) and recovery remain poorly defined. Recent evidence suggests that activin signalling is altered in HF and we hypothesised that follistatins, which are key regulators of activin signalling and which are involved in skeletal muscle regeneration, may be changed in heart failure and contribute to recovery. We examined follistatin (Fst), follistatin-like1 (Fstl1) and follistatin-like3 (Fstl3/FLRG) gene expression by quantitative realtime RT-PCR in myocardial samples obtained from donor organs with good haemodynamic function (n = 9), patients with end-stage dilated cardiomyopathy (DCM, n = 25) and from DCM patients who showed cardiac reverse remodelling and recovery from heart failure following combined mechanical unloading using left ventricular assist device (LVAD) and pharmacologic therapy (LVAD, n = 15). We found a significant increase in both Fstl1 and Fstl3 expression in HF (1.51 ± 0.46 and 2.1 ± 1.0-fold compared to donors respectively, P < 0.005) with levels returning to normal following recovery, whereas Fst levels did not change. Increased Fstl3 levels in HF correlated with skeletal α-actin and BNP, both markers of disease severity,
S147
and were unaltered in response to therapy in LVAD patients who failed to recover. In contrast, Fstl1 levels in HF showed a negative correlation with skeletal α-actin and LVAD implant levels correlated with loss of skeletal α-actin during recovery. The data implicate for the first time Fst3, Fst1 and Fst in the mechanisms underlying heart failure and recovery and open possibilities to new therapeutic tools and targets. Keywords: Growth factors; Heart failure; Cardiac remodelling doi:10.1016/j.yjmcc.2007.03.479
Myocardial remodelling and changes in thyroid hormone receptor α1 early and late after myocardial infarction in rats I. Mourouzis, C. Xinaris, K. Markakis, M. Panagiotou, C. Tesseromatis, C. Pantos, D.V. Cokkinos. Department of Pharmacology and 1st Department of Cardiology, OCSC The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the thyroid hormone receptor α1 (TRα1) receptor. Acute myocardial infarction was induced in rats by ligating the left coronary artery (AMI) while sham operated animals (SHAM) served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype. T3 and T4 levels in plasma were not changed at 2 weeks but T3 was significantly lower and T4 remained unchanged at 13 weeks. TRα1 expression increased 2.0-fold after 13 weeks, P < 0.05 vs. SHAM, while it remained unchanged after 2 weeks. TRβ1 expression decreased 2.2-fold after 13 weeks, P < 0.05, while no change was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TRα1 and 1.6-fold decrease in TRβ1 vs. untreated, P < 0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TRα1 receptor, down-regulation of TRβ1 and lower T3 levels. Thus, apo-TRα1 receptor state may prevail contributing to cardiac fetal phenotype. α1-Adrenergic signalling is, at least in part, involved in this response. Keywords: Remodelling; Thyroid hormone receptors; Adrenergic system doi:10.1016/j.yjmcc.2007.03.480
Thyroid hormone attenuates cardiac remodeling and improves haemodynamics early after myocardial infarction I. Mourouzis, K. Markakis, A. Dimopoulos, C. Xinaris, M. Panagiotou, C. Pantos, D.V. Cokkinos. Department of Pharmacology and 1st Department of Cardiology, OCSC
S148
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
We investigated the effects of thyroid hormone (TH) on cardiac haemodynamics early after myocardial infarction (AMI). TH is shown to reduce left ventricular wall stress (LVWS) due to its effect on cardiomyocyte morphology, while it regulates several genes in the myocardium. AMI rats were treated or not with TH, while sham-operated rats served as controls; AMI-THYR, n = 10, AMI, n = 10 and SHAM, n = 10. Cardiac function was assessed after 2 weeks by echocardiography and in Langendorff preparation. All contractile indexes deteriorated in AMI hearts and significantly improved after TH treatment. LVWS (assessed by the ratio 2*posterior wall thickness/left ventricular diameter in diastole) was significantly increased in AMI hearts, while TH restored it to control. The ratio of α-MHC/β-MHC expression was 1:1 in SHAM vs. 1:2 in AMI hearts, p < 0.05, and 2:1 in AMI-THYR hearts, p < 0.05 vs. SHAM and AMI. Parallel studies in neonatal cardiomyocytes showed that TH significantly increased the ratio of major to minor cell axis and changed their circular shape to an elongated form. This response was accompanied by transient activation of ERK and PD98059 (an inhibitor of ERK), abrogated the TH effect on cell morphology. In conclusion, TH attenuates cardiac remodeling and improves myocardial performance. Changes in contractile protein expression and reduced wall tension due to TH-mediated changes in cell morphology via the activation of ERK kinase signalling may partly account for this response. Keywords: Remodelling; Thyroid hormone; Cardiomyocytes doi:10.1016/j.yjmcc.2007.03.481
Post-myocardial infarction exercise training and myocardial fibrosis John Q. Zhang1, Wenhan Wan1, Lisa Ji1, Anthony S. Powers1, Bryan Wilson1, Yao Sun2. 1Laboratory of Cardiovascular Research, University of Texas-San Antonio. 2Division of Cardiology, University of Tennessee-Memphis After myocardial infarction (MI), cardiac angiotensin converting enzyme (ACE) and angiotensin II are elevated. Locally generated Ang II is contributory to fibrosis in the infarct heart. By using a rat model of MI, we studied the potential effect of post-MI exercise training on cardiac ACE and collagen volume. Rats (7 weeks old) were surgically induced MI [∼40% infarct of the left ventricle (LV)]. After surgery, rats were assigned into 3 groups: (1) MI-exercise (MI-Ex, n = 8), (2) MIsedentary (MI-Sed, n = 8), and (3) sham-operated control (Sham, n = 5). The exercise group started running on a treadmill at 1 week after MI. The rats exercised at 16m/min, 50 min/day and 5 days/week for 8 weeks. Quantitative real-time PCR revealed that ACE mRNA of the non-infarcted LV in MI-Ex rats was lower (P < 0.05) than MI-Sed rats (1.57 ± 0.0.26 vs. 2.48 ± 0.31 compared with Sham). Autoradiographic binding analysis showed that the ACE binding density in the non-infarcted LV of MI-Ex (54.9 ± 2.9) was lower (P < 0.02) than MI-Sed (65.6 ± 3.5) but higher than Sham (38.6 ± 2.5, P < 0.001). ACE binding
density did not differ in the infarcted site of MI-Ex (177 ± 3.1) and MI-Sed (178 ± 2.9). Picrosirius red staining showed that collagen volume of the non-infarcted LV in MI-Sed (1.31 ± 0.11%) was higher (P < 0.005) than both MI-Ex (0.77 ± 0.09%) and Sham (0.62 ± 0.07%) and the latter did not differ from each other. These data suggest that post-MI exercise training significantly lowers the cardiac ACE and attenuates fibrosis in the non-infarcted myocardium. Keywords: Myocardial infarction; Angiotensin converting enzyme; Exercise doi:10.1016/j.yjmcc.2007.03.482
Role of urotensin II signaling in cardiac remodeling Francesco Borgia, Maria Carmen De Angelis, Mariapiera Petretta, Giovanni Esposito, Massimo Chiariello. Federico II University, Naples, Italy Urotensin II (UII) and its receptor are coexpressed in the heart and up-regulated during cardiac dysfunction. However, the effects of UII signaling inhibition on cardiac remodeling in vivo has been poorly studied. To study the in vivo role of UII in the development of heart failure we induced cardiac hypertrophy by transverse aortic constriction (TAC) or myocardial infarction (MI) in wild type mice (WT) following chronic infusion of either UII (2 μmol/kg/die, N = 8), UII inhibitor (Urantide, UR, 2 μmol/kg/die, N = 8) or its vehicle (CON, N = 7) by micro-osmotic pumps. Seven days after TAC or MI, we evaluated MAPK activity as pERK levels by immunoblotting and beta adrenergic receptor kinase 1 (βARK1) levels. Following TAC, left ventricle (LV) mass evaluated as LV weight to body weight ratio (LVW/BW) was significantly reduced in URtreated mice compared to the CON mice (5.7 ± 0.2 vs. 6.5 ± 0.2 p > 0.05) despite a similar trans-stenotic pressure gradient. pERK induction after TAC was prevented by UR treatment (p < 0.05) that led to a significant increase in βARK1 levels. UII signaling inhibition in UR mice led to an impairment of cardiac performance by echocardiography (% fractional shortening, % FS, 45 ± 2 vs. 52 ± 1, p < 0.05) and to a significant increase in % fibrosis (18 ± 1.3 vs. 12 ± 1.2, p < 0.05), compared to control overloaded mice (CON). Strikingly, in vivo UII signaling inhibition was associated with a worse outcome also after MI that led to a significant increase of % infarct size (40 ± 3 vs. 25 ± 4, p < 0.05) and cardiac function deterioration in UR group compared to control infarcted mice. Our data suggest for the first time a potential protective role of UII signaling in the early phase of Heart failure development. Keywords: Miocardial hypertrophy; Cardiac remodeling; Signal transduction doi:10.1016/j.yjmcc.2007.03.483
The aim of the study has been to research the activation of the ET-1 system, ECE, ETA and ETB in ischemic(ICM) and dilated (DCM) end-stage heart failure. The tissue for the study was harvested during a transplantation procedure. Samples from cardiologically healthy donors were taken as control. The study of RNA expression for ET-1 and its converting enzyme with the quantitative RT-PCR method was performed. Protein levels of ET-1, ETA and ETB were measured with the Western Blotting. Results: Both mRNA expression and protein level of ET-1 in l LV from nonfailing donors (NF) and from patients with HF due to ICM were comparable, whereas in those with DCM were higher. The mRNA level for ECE was higher in both ICM and DCM patients. In LV in both groups studied, an elevated level of ETA receptors was found. In DCM, The ETA level was particularly high in patients 35 and 36, who had enlarged LV and large fibrosis. We measured expression of ERK1/2 and p38 kinases. In the case of ERK1/2 no significant differences in activity were found between the patient groups and the controls. Only DCM patients were found to develop an activation of a pathway via p38. Basing on the obtained results we can suppose that the regulation of the endothelin system in the failed heart muscle does not occur only at the RNA level of the gene encoding ET-1 but it occurs at the ECE and ETA levels as well. The fact that p-38 is activated only in DCM proves that ischemic and dilated cardiomyopathies are different pathological entities. Keywords: Heart failure; Gene expression; ET-1 system doi:10.1016/j.yjmcc.2007.03.478
Follistatin gene expression is elevated in heart failure and decreases following recovery E. Lara-Pezzi, L.E. Felkin, E. Birks, M.H. Yacoub, N. Rosenthal, P.J. Barton. Harefield Heart Science Centre, Imperial College London, UK The molecular mechanisms underlying heart failure (HF) and recovery remain poorly defined. Recent evidence suggests that activin signalling is altered in HF and we hypothesised that follistatins, which are key regulators of activin signalling and which are involved in skeletal muscle regeneration, may be changed in heart failure and contribute to recovery. We examined follistatin (Fst), follistatin-like1 (Fstl1) and follistatin-like3 (Fstl3/FLRG) gene expression by quantitative realtime RT-PCR in myocardial samples obtained from donor organs with good haemodynamic function (n = 9), patients with end-stage dilated cardiomyopathy (DCM, n = 25) and from DCM patients who showed cardiac reverse remodelling and recovery from heart failure following combined mechanical unloading using left ventricular assist device (LVAD) and pharmacologic therapy (LVAD, n = 15). We found a significant increase in both Fstl1 and Fstl3 expression in HF (1.51 ± 0.46 and 2.1 ± 1.0-fold compared to donors respectively, P < 0.005) with levels returning to normal following recovery, whereas Fst levels did not change. Increased Fstl3 levels in HF correlated with skeletal α-actin and BNP, both markers of disease severity,
S147
and were unaltered in response to therapy in LVAD patients who failed to recover. In contrast, Fstl1 levels in HF showed a negative correlation with skeletal α-actin and LVAD implant levels correlated with loss of skeletal α-actin during recovery. The data implicate for the first time Fst3, Fst1 and Fst in the mechanisms underlying heart failure and recovery and open possibilities to new therapeutic tools and targets. Keywords: Growth factors; Heart failure; Cardiac remodelling doi:10.1016/j.yjmcc.2007.03.479
Myocardial remodelling and changes in thyroid hormone receptor α1 early and late after myocardial infarction in rats I. Mourouzis, C. Xinaris, K. Markakis, M. Panagiotou, C. Tesseromatis, C. Pantos, D.V. Cokkinos. Department of Pharmacology and 1st Department of Cardiology, OCSC The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the thyroid hormone receptor α1 (TRα1) receptor. Acute myocardial infarction was induced in rats by ligating the left coronary artery (AMI) while sham operated animals (SHAM) served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype. T3 and T4 levels in plasma were not changed at 2 weeks but T3 was significantly lower and T4 remained unchanged at 13 weeks. TRα1 expression increased 2.0-fold after 13 weeks, P < 0.05 vs. SHAM, while it remained unchanged after 2 weeks. TRβ1 expression decreased 2.2-fold after 13 weeks, P < 0.05, while no change was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TRα1 and 1.6-fold decrease in TRβ1 vs. untreated, P < 0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TRα1 receptor, down-regulation of TRβ1 and lower T3 levels. Thus, apo-TRα1 receptor state may prevail contributing to cardiac fetal phenotype. α1-Adrenergic signalling is, at least in part, involved in this response. Keywords: Remodelling; Thyroid hormone receptors; Adrenergic system doi:10.1016/j.yjmcc.2007.03.480
Thyroid hormone attenuates cardiac remodeling and improves haemodynamics early after myocardial infarction I. Mourouzis, K. Markakis, A. Dimopoulos, C. Xinaris, M. Panagiotou, C. Pantos, D.V. Cokkinos. Department of Pharmacology and 1st Department of Cardiology, OCSC
S148
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
We investigated the effects of thyroid hormone (TH) on cardiac haemodynamics early after myocardial infarction (AMI). TH is shown to reduce left ventricular wall stress (LVWS) due to its effect on cardiomyocyte morphology, while it regulates several genes in the myocardium. AMI rats were treated or not with TH, while sham-operated rats served as controls; AMI-THYR, n = 10, AMI, n = 10 and SHAM, n = 10. Cardiac function was assessed after 2 weeks by echocardiography and in Langendorff preparation. All contractile indexes deteriorated in AMI hearts and significantly improved after TH treatment. LVWS (assessed by the ratio 2*posterior wall thickness/left ventricular diameter in diastole) was significantly increased in AMI hearts, while TH restored it to control. The ratio of α-MHC/β-MHC expression was 1:1 in SHAM vs. 1:2 in AMI hearts, p < 0.05, and 2:1 in AMI-THYR hearts, p < 0.05 vs. SHAM and AMI. Parallel studies in neonatal cardiomyocytes showed that TH significantly increased the ratio of major to minor cell axis and changed their circular shape to an elongated form. This response was accompanied by transient activation of ERK and PD98059 (an inhibitor of ERK), abrogated the TH effect on cell morphology. In conclusion, TH attenuates cardiac remodeling and improves myocardial performance. Changes in contractile protein expression and reduced wall tension due to TH-mediated changes in cell morphology via the activation of ERK kinase signalling may partly account for this response. Keywords: Remodelling; Thyroid hormone; Cardiomyocytes doi:10.1016/j.yjmcc.2007.03.481
Post-myocardial infarction exercise training and myocardial fibrosis John Q. Zhang1, Wenhan Wan1, Lisa Ji1, Anthony S. Powers1, Bryan Wilson1, Yao Sun2. 1Laboratory of Cardiovascular Research, University of Texas-San Antonio. 2Division of Cardiology, University of Tennessee-Memphis After myocardial infarction (MI), cardiac angiotensin converting enzyme (ACE) and angiotensin II are elevated. Locally generated Ang II is contributory to fibrosis in the infarct heart. By using a rat model of MI, we studied the potential effect of post-MI exercise training on cardiac ACE and collagen volume. Rats (7 weeks old) were surgically induced MI [∼40% infarct of the left ventricle (LV)]. After surgery, rats were assigned into 3 groups: (1) MI-exercise (MI-Ex, n = 8), (2) MIsedentary (MI-Sed, n = 8), and (3) sham-operated control (Sham, n = 5). The exercise group started running on a treadmill at 1 week after MI. The rats exercised at 16m/min, 50 min/day and 5 days/week for 8 weeks. Quantitative real-time PCR revealed that ACE mRNA of the non-infarcted LV in MI-Ex rats was lower (P < 0.05) than MI-Sed rats (1.57 ± 0.0.26 vs. 2.48 ± 0.31 compared with Sham). Autoradiographic binding analysis showed that the ACE binding density in the non-infarcted LV of MI-Ex (54.9 ± 2.9) was lower (P < 0.02) than MI-Sed (65.6 ± 3.5) but higher than Sham (38.6 ± 2.5, P < 0.001). ACE binding
density did not differ in the infarcted site of MI-Ex (177 ± 3.1) and MI-Sed (178 ± 2.9). Picrosirius red staining showed that collagen volume of the non-infarcted LV in MI-Sed (1.31 ± 0.11%) was higher (P < 0.005) than both MI-Ex (0.77 ± 0.09%) and Sham (0.62 ± 0.07%) and the latter did not differ from each other. These data suggest that post-MI exercise training significantly lowers the cardiac ACE and attenuates fibrosis in the non-infarcted myocardium. Keywords: Myocardial infarction; Angiotensin converting enzyme; Exercise doi:10.1016/j.yjmcc.2007.03.482
Role of urotensin II signaling in cardiac remodeling Francesco Borgia, Maria Carmen De Angelis, Mariapiera Petretta, Giovanni Esposito, Massimo Chiariello. Federico II University, Naples, Italy Urotensin II (UII) and its receptor are coexpressed in the heart and up-regulated during cardiac dysfunction. However, the effects of UII signaling inhibition on cardiac remodeling in vivo has been poorly studied. To study the in vivo role of UII in the development of heart failure we induced cardiac hypertrophy by transverse aortic constriction (TAC) or myocardial infarction (MI) in wild type mice (WT) following chronic infusion of either UII (2 μmol/kg/die, N = 8), UII inhibitor (Urantide, UR, 2 μmol/kg/die, N = 8) or its vehicle (CON, N = 7) by micro-osmotic pumps. Seven days after TAC or MI, we evaluated MAPK activity as pERK levels by immunoblotting and beta adrenergic receptor kinase 1 (βARK1) levels. Following TAC, left ventricle (LV) mass evaluated as LV weight to body weight ratio (LVW/BW) was significantly reduced in URtreated mice compared to the CON mice (5.7 ± 0.2 vs. 6.5 ± 0.2 p > 0.05) despite a similar trans-stenotic pressure gradient. pERK induction after TAC was prevented by UR treatment (p < 0.05) that led to a significant increase in βARK1 levels. UII signaling inhibition in UR mice led to an impairment of cardiac performance by echocardiography (% fractional shortening, % FS, 45 ± 2 vs. 52 ± 1, p < 0.05) and to a significant increase in % fibrosis (18 ± 1.3 vs. 12 ± 1.2, p < 0.05), compared to control overloaded mice (CON). Strikingly, in vivo UII signaling inhibition was associated with a worse outcome also after MI that led to a significant increase of % infarct size (40 ± 3 vs. 25 ± 4, p < 0.05) and cardiac function deterioration in UR group compared to control infarcted mice. Our data suggest for the first time a potential protective role of UII signaling in the early phase of Heart failure development. Keywords: Miocardial hypertrophy; Cardiac remodeling; Signal transduction doi:10.1016/j.yjmcc.2007.03.483