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Myocardial diastolic dysfunction at experimental diabetes mellitus—the role of nitric oxide
ABSTRACTS / Journal of Molecular and Cellular Cardiology 40 (2006) 920 – 1015
this effect. PGE2 markedly increases the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. Thus, in ventricular cardiomyocytes, ERK1/2 appears to be essential for PGE2-induced hypertrophic and antiapoptotic responses. doi:10.1016/j.yjmcc.2006.03.252
238. Myocardial diastolic dysfunction at experimental diabetes mellitusthe role of nitric oxide Vadim F. Sagach, Oleksandra D. Prysyazhna. Bogomoletz Institute of Physiology NAS of Ukraine The clinical investigations shows that myocardial diastolic dysfunction develops already at early stages of I type diabetes mellitus. The purpose of our work was to reveal disturbances of myocardial relaxation function in rats with streptozotocininduced diabetes and to investigate possible mechanisms of such infringements development. On Langendorff isolated heart, the essential increase of left ventricular diastolic stiffness (considered as DEDP/DV) was shown at experimental diabetes. At dosed left ventricular stretching with balloon, the sharp growth of EDP meanings in diabetic hearts was observed at significantly smaller value of balloon volume gain, than in control hearts. These phenomena were accompanied with reduction of FrancStarling curve phase plateau extension (on 60 %). Concurrently with such disturbances was demonstrated the endothelial dysfunction development with depression of coronary vessels endothelium-dependent dilatation; reduction of NOS activity in 3.7 times, including 12-fold reduction of cNOS activity; decrease of nitric oxide metabolite nitrite-anion contents in 10.5 times. The similar effects were registered at perfusion with hyperglycemic solution (glucose39 M/l) or with NOS inhibitorl-NAME (105 M/l). Long-term feeding with NO larginine (for 14 days, 25mg/kg per day), leads to the particular recovery of myocardial function and endothelium-dependent dilatation of coronary vessels. Thus, chronic hyperglycemia and depression of nitric oxide synthesis play an important role in myocardial diastolic dysfunction development at experimental diabetes mellitus type I. doi:10.1016/j.yjmcc.2006.03.253
239. Gram positive bacteria reduce viability and contraction of isolated cardiomyocytes: Role of endothelin-1 Trupti A. Patel a, Jane A. Mitchell a, Timothy D. Warner b, Sia˜n E. Harding a. a Myocardial Systems Biology and Cardiothoracic Pharmacology, Critical Care, NHLI, Imperial College London, UK. b The William Harvey Research Institute, Barts and the London, UK Aim: The pathophysiology of myocardial contractile dysfunction in sepsis is incompletely understood. We aimed
1007
to characterise the morphology and contractility changes induced by direct exposure of cardiomyocytes to heat-killed, Staphylococcus aureus (SA), bacteria in vitro. The role of endothelin (ET) was investigated since it is suspected to play a key role in septic myocardial depression. Methods: Adult rat ventricular myocytes were cultured for 24 or 48h with SA, ET-1 or ET-3, with and without the selective ETA receptor antagonist ABT-627. Proportions of viable (rodshaped or hypercontracted) and non-viable myocytes were calculated. Cells were stimulated to contract (0.5Hz, 1mM Ca2+) and proportions of contracting, non-contracting and arrhythmic cells were counted. Results: At 24h, SA decreased the percentage of rodshaped myocytes compared to control (Con 43.8 T 3.4%, SA 22.9 T 4.5%, P < 0.05, n = 5), with concomitant increases in both hypercontracted and non-viable myocytes. SA reduced the proportion of viable myocytes that had contractile activity at 24 (n = 33) and 48 (n = 9) h. Contraction amplitude of contracting myocytes was not significantly different between groups. Culturing with ABT-627 (108M) prevented the decrease in the proportion of contracting cells induced by SA, at both 24 and 48h (n = 7). ET-1 and ET-3 (1097M) resulted in a reduced population of viable myocytes. ET1 (108M) at 48h, but not at 24h, reduced the proportion of contracting cells. However, the reduction was not as great as observed with SA. Conclusion: Direct contact with bacteria damages the cardiac myocyte. This effect is, in part, mediated by ET-1 acting through ETA receptors. doi:10.1016/j.yjmcc.2006.03.254
240. Human cardiac cells express GM-CSF under inflammatory conditions—Possible implications for cell differentiation and angiogenesis P.J. Hohensinner a, C. Kaun a, K. Rychli a, G. Maurer a, K. Huber b, J. Wojta a. a Medical, University of Vienna, Vienna, Austria. b Wilheminenhospital, Vienna, Austria Introduction: Novel therapies of myocardial infarction include stem cell mobilization and stem cell therapy although little is known about the cytokine environment provided by the heart to augment survival and direct differentiation of stem cells. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been identified as an important contributor to monocyte and macrophage survival, stem cell differentiation and angiogenesis. Therefore, the aim of our study was to determine if GM-CSF is expressed in cardiac cells in vitro and if inflammation regulates its expression. Results: Human Adult Cardiac Myocytes (HACM) and Human Adult Cardiac Fibroblasts (HACF) were incubated with Tumor Necrosis Factor-alpha (TNF-alpha) to simulate inflammatory conditions. TNF-alpha dose-dependently increased the expression of GM-CSF in both cell types. TNFalpha induced expression of GM-CSF was also confirmed on
this effect. PGE2 markedly increases the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. Thus, in ventricular cardiomyocytes, ERK1/2 appears to be essential for PGE2-induced hypertrophic and antiapoptotic responses. doi:10.1016/j.yjmcc.2006.03.252
238. Myocardial diastolic dysfunction at experimental diabetes mellitusthe role of nitric oxide Vadim F. Sagach, Oleksandra D. Prysyazhna. Bogomoletz Institute of Physiology NAS of Ukraine The clinical investigations shows that myocardial diastolic dysfunction develops already at early stages of I type diabetes mellitus. The purpose of our work was to reveal disturbances of myocardial relaxation function in rats with streptozotocininduced diabetes and to investigate possible mechanisms of such infringements development. On Langendorff isolated heart, the essential increase of left ventricular diastolic stiffness (considered as DEDP/DV) was shown at experimental diabetes. At dosed left ventricular stretching with balloon, the sharp growth of EDP meanings in diabetic hearts was observed at significantly smaller value of balloon volume gain, than in control hearts. These phenomena were accompanied with reduction of FrancStarling curve phase plateau extension (on 60 %). Concurrently with such disturbances was demonstrated the endothelial dysfunction development with depression of coronary vessels endothelium-dependent dilatation; reduction of NOS activity in 3.7 times, including 12-fold reduction of cNOS activity; decrease of nitric oxide metabolite nitrite-anion contents in 10.5 times. The similar effects were registered at perfusion with hyperglycemic solution (glucose39 M/l) or with NOS inhibitorl-NAME (105 M/l). Long-term feeding with NO larginine (for 14 days, 25mg/kg per day), leads to the particular recovery of myocardial function and endothelium-dependent dilatation of coronary vessels. Thus, chronic hyperglycemia and depression of nitric oxide synthesis play an important role in myocardial diastolic dysfunction development at experimental diabetes mellitus type I. doi:10.1016/j.yjmcc.2006.03.253
239. Gram positive bacteria reduce viability and contraction of isolated cardiomyocytes: Role of endothelin-1 Trupti A. Patel a, Jane A. Mitchell a, Timothy D. Warner b, Sia˜n E. Harding a. a Myocardial Systems Biology and Cardiothoracic Pharmacology, Critical Care, NHLI, Imperial College London, UK. b The William Harvey Research Institute, Barts and the London, UK Aim: The pathophysiology of myocardial contractile dysfunction in sepsis is incompletely understood. We aimed
1007
to characterise the morphology and contractility changes induced by direct exposure of cardiomyocytes to heat-killed, Staphylococcus aureus (SA), bacteria in vitro. The role of endothelin (ET) was investigated since it is suspected to play a key role in septic myocardial depression. Methods: Adult rat ventricular myocytes were cultured for 24 or 48h with SA, ET-1 or ET-3, with and without the selective ETA receptor antagonist ABT-627. Proportions of viable (rodshaped or hypercontracted) and non-viable myocytes were calculated. Cells were stimulated to contract (0.5Hz, 1mM Ca2+) and proportions of contracting, non-contracting and arrhythmic cells were counted. Results: At 24h, SA decreased the percentage of rodshaped myocytes compared to control (Con 43.8 T 3.4%, SA 22.9 T 4.5%, P < 0.05, n = 5), with concomitant increases in both hypercontracted and non-viable myocytes. SA reduced the proportion of viable myocytes that had contractile activity at 24 (n = 33) and 48 (n = 9) h. Contraction amplitude of contracting myocytes was not significantly different between groups. Culturing with ABT-627 (108M) prevented the decrease in the proportion of contracting cells induced by SA, at both 24 and 48h (n = 7). ET-1 and ET-3 (1097M) resulted in a reduced population of viable myocytes. ET1 (108M) at 48h, but not at 24h, reduced the proportion of contracting cells. However, the reduction was not as great as observed with SA. Conclusion: Direct contact with bacteria damages the cardiac myocyte. This effect is, in part, mediated by ET-1 acting through ETA receptors. doi:10.1016/j.yjmcc.2006.03.254
240. Human cardiac cells express GM-CSF under inflammatory conditions—Possible implications for cell differentiation and angiogenesis P.J. Hohensinner a, C. Kaun a, K. Rychli a, G. Maurer a, K. Huber b, J. Wojta a. a Medical, University of Vienna, Vienna, Austria. b Wilheminenhospital, Vienna, Austria Introduction: Novel therapies of myocardial infarction include stem cell mobilization and stem cell therapy although little is known about the cytokine environment provided by the heart to augment survival and direct differentiation of stem cells. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been identified as an important contributor to monocyte and macrophage survival, stem cell differentiation and angiogenesis. Therefore, the aim of our study was to determine if GM-CSF is expressed in cardiac cells in vitro and if inflammation regulates its expression. Results: Human Adult Cardiac Myocytes (HACM) and Human Adult Cardiac Fibroblasts (HACF) were incubated with Tumor Necrosis Factor-alpha (TNF-alpha) to simulate inflammatory conditions. TNF-alpha dose-dependently increased the expression of GM-CSF in both cell types. TNFalpha induced expression of GM-CSF was also confirmed on