Abstract 3648: A Dual Role for Granulocyte-Colony Stimulating Factor in Promotion of Coronary Collateral Growth and Production of Cardiomyocyte Reactive Oxygen Species

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ana C Carrão ◽  
Wiliam M Chilian ◽  
June Yun ◽  
Chris Kolz ◽  
Ivo Buschmann
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiac Myocytes ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Coronary Collateral ◽  
Collateral Growth ◽  
Coronary Collateral Growth ◽  
Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophil progenitors. Because G-CSF ameliorates myocar-dial ischemic injury, we projected this effect would also translate into stimulating myocardial adaptations to ischemia. Accordingly, we hypothesized that G-CSF stimulates coronary collateral growth (CCG) in a rat model of repetitive episodic ischemia (RI): 40 sec LAD occlusion every 20 min for 2h20min, 3 times/day for 5 days. CCG was deduced from collateral-dependent flow (flow to LAD region during occlusion [neutron activated microspheres]) and expressed as the increase in the ratio between collateral-dependent and normal zone flows from the initial measurement to that after 5 days of RI. Following RI, G-CSF (100 microg/Kg/day) increased CCG (P<0.01) (0.47 +− 0.15) versus vehicle (0.14 +− 0.06). Surprisingly, G-CSF treatment without RI increased CCG (0.57 +− 0.18, P<0.01 vs vehicle) equal to G-CSF +RI. Because redox signaling is critical for CCG and neutrophils are a rich source of NADPH oxidase and reactive oxygen species (ROS), we hypothesized that G-CSF stimulates production of ROS. We evaluated ROS by dihydroethidine (DHE) fluorescence (LV injection, 60 microg/kg, during two episodes of ischemia). DHE fluorescence was double in G-CSF+RI vs vehicle+RI (P<0.01), and even higher in G-CSF without RI (P<0.01). Interestingly, the DHE signal did not co-localize with myeloperoxidase (immunostaining, neutrophil marker) but appeared in cardiac myocytes. To unequivocally determine if G-CSF stimulates ROS production in cardiac myocytes, we studied isolated cardiac myocytes and found the cytokine stimulates ROS. In addition to affecting neutrophils, G-CSF directly targets cardiac myocytes to produce ROS. In conclusion, G-CSF stimulates production of ROS by cardiac myocytes, which likely plays a pivotal role in adaptations of the heart to ischemia including growth of the coronary collateral circulation.

scholarly journals Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species

2021 ◽  
Vol 12 ◽  
Author(s):  
Katiria Soto-Diaz ◽  
Mario Vailati-Riboni ◽  
Allison Y. Louie ◽  
Daniel B. McKim ◽  
H. Rex Gaskins ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Adult Brain ◽  
Oxygen Species ◽  
Colony Stimulating Factor ◽  
Sequencing Data ◽  
Body Weights ◽  
Burrowing Behavior ◽  
Dose Dependent ◽  
Stimulating Factor

Microglia activation and proliferation are hallmarks of many neurodegenerative disorders and may contribute to disease pathogenesis. Neurons actively regulate microglia survival and function, in part by secreting the microglia mitogen interleukin (IL)-34. Both IL-34 and colony stimulating factor (CSF)-1 bind colony stimulating factor receptor (CSFR)1 expressed on microglia. Systemic treatment with central nervous system (CNS) penetrant, CSFR1 antagonists, results in microglia death in a dose dependent matter, while others, such as GW2580, suppress activation during disease states without altering viability. However, it is not known how treatment with non-penetrant CSF1R antagonists, such as GW2580, affect the normal physiology of microglia. To determine how GW2580 affects microglia function, C57BL/6J mice were orally gavaged with vehicle or GW2580 (80mg/kg/d) for 8 days. Body weights and burrowing behavior were measured throughout the experiment. The effects of GW2580 on circulating leukocyte populations, brain microglia morphology, and the transcriptome of magnetically isolated adult brain microglia were determined. Body weights, burrowing behavior, and circulating leukocytes were not affected by treatment. Analysis of Iba-1 stained brain microglia indicated that GW2580 treatment altered morphology, but not cell number. Analysis of RNA-sequencing data indicated that genes related to reactive oxygen species (ROS) regulation and survival were suppressed by treatment. Treatment of primary microglia cultures with GW2580 resulted in a dose-dependent reduction in viability only when the cells were concurrently treated with LPS, an inducer of ROS. Pre-treatment with the ROS inhibitor, YCG063, blocked treatment induced reductions in viability. Finally, GW2580 sensitized microglia to hydrogen peroxide induced cell death. Together, these data suggest that partial CSF1R antagonism may render microglia more susceptible to reactive oxygen and nitrogen species.

scholarly journals The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth

2013 ◽  
Vol 305 (9) ◽  
pp. H1275-H1280 ◽  
Author(s):  
Yuh Fen Pung ◽  
Wai Johnn Sam ◽  
James P. Hardwick ◽  
Liya Yin ◽  
Vahagn Ohanyan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Synthesis ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Energy Production ◽  
Phenotypic Switching ◽  
Oxygen Species ◽  
Coronary Collateral ◽  
Collateral Growth

Coronary collateral growth is a process involving coordination between growth factors expressed in response to ischemia and mechanical forces. Underlying this response is proliferation of vascular smooth muscle and endothelial cells, resulting in an enlargement in the caliber of arterial-arterial anastomoses, i.e., a collateral vessel, sometimes as much as an order of magnitude. An integral element of this cell proliferation is the process known as phenotypic switching in which cells of a particular phenotype, e.g., contractile vascular smooth muscle, must change their phenotype to proliferate. Phenotypic switching requires that protein synthesis occurs and different kinase signaling pathways become activated, necessitating energy to make the switch. Moreover, kinases, using ATP to phosphorylate their targets, have an energy requirement themselves. Mitochondria play a key role in the energy production that enables phenotypic switching, but under conditions where mitochondrial energy production is constrained, e.g., mitochondrial oxidative stress, this switch is impaired. In addition, we discuss the potential importance of uncoupling proteins as modulators of mitochondrial reactive oxygen species production and bioenergetics, as well as the role of AMP kinase as an energy sensor upstream of mammalian target of rapamycin, the master regulator of protein synthesis.

scholarly journals Glycated Proteins Stimulate Reactive Oxygen Species Production in Cardiac Myocytes

Circulation ◽  
2006 ◽  
Vol 113 (9) ◽  
pp. 1235-1243 ◽  
Author(s):  
Min Zhang ◽  
Ay Lin Kho ◽  
Narayana Anilkumar ◽  
Rakesh Chibber ◽  
Patrick J. Pagano ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiac Myocytes ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Glycated Proteins ◽  
Species Production
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