Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · Jun 2007
HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia.
Hypoxia inducible factor-1alpha (HIF-1alpha) is a proangiogenic transcription factor stabilized and activated under hypoxia. It regulates the expression of numerous target genes, including vascular endothelial growth factor (VEGF) and other cytoprotective proteins. In this study, we hypothesized that bone marrow stem cells (BMSCs) secrete growth factors which protect cardiomyocytes via HIF-1alpha pathway. ⋯ The increase and translocation of HIF-1alpha in BMSCs were completely blocked by 2-methoxyestradiol (2-ME2; 5 mumol), a HIF-1alpha inhibitor. Moreover, the protection of cardiomyocytes by BMSC and VEGF secretion was abolished by neutralizing HIF-1alpha antibody in a concentration dependent manner (200-3200 ng/ml). Bone marrow stem cells protect cardiomyocytes by up-regulation of VEGF via activating HIF-1alpha.
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J. Mol. Cell. Cardiol. · Mar 2007
Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins.
Beta-adrenergic receptor (beta-AR) stimulation induces apoptosis in adult rat ventricular myocytes (ARVM). beta1 integrin signaling plays a protective role in beta-AR-stimulated apoptosis. Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional serine/threonine kinase, negatively regulates cardiac hypertrophy. Here we show that beta-AR stimulation (isoproterenol; 15 min) increases tyr(216) phosphorylation and GSK-3beta activity. ⋯ These data suggest that beta-AR stimulation increases GSK-3beta activity. Activation of GSK-3beta plays a pro-apoptotic role in beta-AR-stimulated apoptosis via the involvement of mitochondrial death pathway. beta1 integrins inactivate GSK-3beta and play an anti-apoptotic role via the involvement of PI3-kinase pathway. The apoptotic effects of GSK-3beta may be mediated, at least in part, via its nuclear localization and induction of pro-apoptotic genes, such as Gadd153.
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J. Mol. Cell. Cardiol. · Aug 2006
Comparative StudyA critical cytoprotective role of endogenous adrenomedullin in acute myocardial infarction.
Exogenous administration or transfection of adrenomedullin (AM) affords protection against ischaemia-reperfusion injury. Here we have examined the role of endogenous AM in regulating the development of myocardial infarction. Wild type (WT) and AM(+/-) mice underwent 30 min regional myocardial ischaemia and 120 min reperfusion. ⋯ Treatment with exogenous recombinant AM (200 ng/kg) prior to coronary occlusion rescued the ischaemia-reperfusion intolerant phenotype of AM(+/-) mice and further limited infarct development in WT mice. Administration of recombinant AM was associated with augmented phosphorylation of Akt and eNOS in early reperfusion suggesting a role for AM in regulating this survival pathway. These studies provide the first evidence that expression of AM is a critical factor regulating myocardial tolerance to ischaemia-reperfusion injury.
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J. Mol. Cell. Cardiol. · Jan 2006
Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes.
The possible role of hydrogen sulfide (H2S) in cardioprotection was investigated in isolated rat ventricular myocytes exposed to severe metabolic inhibition (MI) in glucose-free buffer containing 2-deoxy-D-glucose (2-DOG), an inhibitor of glycolysis. Pretreatment (30 min) with NaHS (a H2S donor) at concentrations of 10(-5) to 10(-4) mol/L caused a concentration related increase in cell viability and the ratio of rod-shaped cells. A time course study showed that NaHS-induced cardioprotection occurred in 2 time windows (approximately 1 h and 16-28 h). ⋯ The cardioprotective effects of NaHS were significantly attenuated by glibenclamide and HMR-1098 treatment but not by 5-HD. Inhibition of NO production with L-NG nitroarginine methyl ester (L-NAME) also attenuated the cardioprotection of NaHS. In conclusion, our findings provide the first evidence that H2S may protect the heart most probably by activating sarcolemmal KATP channels and/or provoking NO release and the cardioprotective effects of metabolic ischemic preconditioning is, at least partially, mediated by endogenous H2S.