Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction.
alpha Subunit/metabolism; Amino Acids; Animal; Animals; Apoptosis/drug effects; Cardiotonic Agents/*pharmacology; Cell Hypoxia; Cell Line; CXCR4/deficiency/genetics/*metabolism; Dicarboxylic/*pharmacology; Disease Models; Enzyme Inhibitors/pharmacology; hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors/metabolism; Inbred C57BL; Knockout; Left/*drug effects; Mice; myocardial infarction; Myocardial Infarction/*drug therapy/genetics/metabolism/pathology/physiopathology; Myocardium/*metabolism/pathology; Rats; Receptors; Recovery of Function; Signal Transduction/drug effects; stem cells; Stem Cells/drug effects/metabolism; Stroke Volume/drug effects; Time Factors; Up-Regulation; Ventricular Function
The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased
Mayorga Mari; Kiedrowski Matthew; Shamhart Patricia; Forudi Farhad; Weber Kristal; Chilian William M; Penn Marc S; Dong Feng
American journal of physiology. Heart and circulatory physiology
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00449.2015" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00449.2015</a>
Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts.
*Cell Differentiation; Animals; Blood Glucose/metabolism; cardiac fibroblast; Cell Movement; Cell Proliferation; Cells; collagen; Collagen/metabolism; collagene; concentration elevee de glucose; Cultured; diabete; diabetes; fibroblaste cardiaque; Fibroblasts/*metabolism/pathology; Fibrosis; high glucose; Hyperglycemia/*metabolism/pathology; Male; migration; Myocardium/*metabolism/pathology; myofibroblast; myofibroblastes; proliferation; Rats; Signal Transduction; Sprague-Dawley
Diabetes is an independent risk factor for cardiovascular disease that can eventually cause cardiomyopathy and heart failure. Cardiac fibroblasts (CF) are the critical mediators of physiological and pathological cardiac remodeling; however, the effects of hyperglycemia on cardiac fibroblast function and differentiation is not well known. Here, we performed a comprehensive investigation on the effects of hyperglycemia on cardiac fibroblasts and show that hyperglycemia enhances cardiac fibroblast function and differentiation. We found that high glucose treatment increased collagen I, III, and VI gene expression in rat adult cardiac fibroblasts. Interestingly, hyperglycemia increased CF migration and proliferation that is augmented by collagen I and III. Surprisingly, we found that short term hyperglycemia transiently inhibited ERK1/2 activation but increased AKT phosphorylation. Finally, high glucose treatment increased spontaneous differentiation of cardiac fibroblasts to myofibroblasts with increasing passage compared with low glucose. Taken together, these findings suggest that hyperglycemia induces cardiac fibrosis by modulating collagen expression, migration, proliferation, and differentiation of cardiac fibroblasts.
Shamhart Patricia E; Luther Daniel J; Adapala Ravi K; Bryant Jennifer E; Petersen Kyle A; Meszaros J Gary; Thodeti Charles K
Canadian journal of physiology and pharmacology
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1139/cjpp-2013-0490" target="_blank" rel="noreferrer noopener">10.1139/cjpp-2013-0490</a>
Impairment of pH gradient and membrane potential mediates redox dysfunction in the mitochondria of the post-ischemic heart.
*Energy Metabolism; *Membrane potential; *Membrane Potential; *Mitochondria; *Myocardial ischemia and reperfusion; *Oxidative Stress; *pH gradient; *Redox dysfunction; Aconitate Hydratase/metabolism; Animal; Animals; Cell Line; Disease Models; Electron Transport Chain Complex Proteins/metabolism; Heart/*metabolism/pathology; Hydrogen Peroxide/metabolism; Hydrogen-Ion Concentration; Ionophores/pharmacology; Male; Mitochondria; Mitochondrial; Myocardial Infarction/*metabolism/pathology; Myocardium/*metabolism/pathology; Oxidation-Reduction; Potassium/metabolism; Rats; Sprague-Dawley; Superoxides/metabolism
The mitochondrial electrochemical gradient (Deltap), which comprises the pH gradient (DeltapH) and the membrane potential (DeltaPsi), is crucial in controlling energy transduction. During myocardial ischemia and reperfusion (IR), mitochondrial dysfunction mediates superoxide ((.)O2(-)) and H2O2 overproduction leading to oxidative injury. However, the role of DeltapH and DeltaPsi in post-ischemic injury is not fully established. Here we studied mitochondria from the risk region of rat hearts subjected to 30 min of coronary ligation and 24 h of reperfusion in vivo. In the presence of glutamate, malate and ADP, normal mitochondria (mitochondria of non-ischemic region, NR) exhibited a heightened state 3 oxygen consumption rate (OCR) and reduced (.)O2(-) and H2O2 production when compared to state 2 conditions. Oligomycin (increases DeltapH by inhibiting ATP synthase) increased (.)O2(-) and H2O2 production in normal mitochondria, but not significantly in the mitochondria of the risk region (IR mitochondria or post-ischemic mitochondria), indicating that normal mitochondrial (.)O2(-) and H2O2 generation is dependent on DeltapH and that IR impaired the DeltapH of normal mitochondria. Conversely, nigericin (dissipates DeltapH) dramatically reduced (.)O2(-) and H2O2 generation by normal mitochondria under state 4 conditions, and this nigericin quenching effect was less pronounced in IR mitochondria. Nigericin also increased mitochondrial OCR, and predisposed normal mitochondria to a more oxidized redox status assessed by increased oxidation of cyclic hydroxylamine, CM-H. IR mitochondria, although more oxidized than normal mitochondria, were not responsive to nigericin-induced CM-H oxidation, which is consistent with the result that IR induced DeltapH impairment in normal mitochondria. Valinomycin, a K(+) ionophore used to dissipate DeltaPsi, drastically diminished (.)O2(-) and H2O2 generation by normal mitochondria, but less pronounced effect on IR mitochondria under state 4 conditions, indicating that DeltaPsi also contributed to (.)O2(-) generation by normal mitochondria and that IR mediated DeltaPsi impairment. However, there was no significant difference in valinomycin-induced CM-H oxidation between normal and IR mitochondria. In conclusion, under normal conditions the proton backpressure imposed by DeltapH restricts electron flow, controls a limited amount of (.)O2(-) generation, and results in a more reduced myocardium; however, IR causes DeltapH impairment and prompts a more oxidized myocardium.
Kang Patrick T; Chen Chwen-Lih; Lin Paul; Chilian William M; Chen Yeong-Renn
Basic research in cardiology
2017
2017-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-017-0626-1" target="_blank" rel="noreferrer noopener">10.1007/s00395-017-0626-1</a>