Stimulation of coronary collateral growth by granulocyte stimulating factor: role of reactive oxygen species.

Abstract

OBJECTIVE:

The purpose of this study was to determine whether G-CSF promotes coronary collateral growth (CCG) and decipher the mechanism for this stimulation.

METHODS AND RESULTS:

In a rat model of repetitive episodic myocardial ischemia (RI, 40 seconds LAD occlusion every 20 minutes for 2 hours and 20 minutes, 3 times/d for 5 days) CCG was deduced from collateral-dependent flow (flow to LAD region during occlusion). After RI, G-CSF (100 microg/kg/d) 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) equal to G-CSF+RI. 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 versus vehicle+RI (P<0.01), and even higher in G-CSF without RI (P<0.01). Interestingly, the DHE signal did not colocalize with myeloperoxidase (immunostaining, neutrophil marker) but appeared in cardiac myocytes. The study of isolated cardiac myocytes revealed the cytokine stimulates ROS which elicit production of angiogenic factors. Apocynin inhibited G-CSF effects both in vivo and in vitro.

CONCLUSIONS:

G-CSF stimulates ROS production directly in cardiomyocytes, which plays a pivotal role in triggering adaptations of the heart to ischemia including growth of the coronary collaterals.

• Authors: Ana Catarina R Carrão, William M Chilian, June Yun, Christopher Kolz, Petra Rocic, Kerstin Lehmann, Jeroen P H M van den Wijngaard, Pepijn van Horssen, Jos A E Spaan, Vahagn Ohanyan, Yuh Fen Pung, Ivo Buschmann
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 11 Pg. 1817-22 (Nov 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19542022 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Granulocyte Colony-Stimulating Factor

Topics

• Analysis of Variance
• Animals
• Cells, Cultured
• Collateral Circulation (drug effects, physiology)
• Coronary Circulation (drug effects)
• Disease Models, Animal
• Echocardiography
• Granulocyte Colony-Stimulating Factor (metabolism, pharmacology)
• Heart Function Tests
• Humans
• Immunohistochemistry
• Male
• Myocardial Ischemia (diagnostic imaging, drug therapy, metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism)
• Probability
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Reference Values