Coronary microvascular dysfunction in the setting of chronic ischemia is independent of arginase activity.
BACKGROUND
Chronic myocardial ischemia induces endothelial dysfunction in the coronary microcirculation resulting in impaired nitric oxide signaling. This dysfunction has wide-ranging effects including impaired tissue perfusion and is implicated in impairment of the angiogenic process in settings of endothelial dysfunction. We hypothesized chronic myocardial ischemia results in increased activity of Arginase I, diminishing bioavailability of l-arginine, the substrate for endothelial nitric oxide production.


METHODS
Chronic myocardial ischemia was induced for 7-weeks in 6 Yucatan miniswine utilizing an ameroid constrictor placed around the left circumflex coronary artery. Ischemic and non-ischemic tissue was harvested at the 7-week time point. Expression of Arginase I, eNOS, and phospho-eNOS was assessed utilizing Western blotting. Arginase activity was measured. Immunofluorescent staining assessed expression of Arginase I between ischemic and non-ischemic microvessels. Coronary microvascular relaxation studies were performed.


RESULTS
Arginase I expression, activity, and staining was similar between ischemic and non-ischemic territories. Significant impairments in coronary microvascular relaxation were observed in microvessels from the ischemic territory in response to endothelial-dependent agents but remained similar between territories in response to endothelial independent agents. Regression analysis between arginase activity and degree of microvascular vasorelaxation demonstrated no significant correlation.


CONCLUSIONS
Coronary microvascular dysfunction in the setting of chronic myocardial ischemia occurs independently of Arginase I activity and expression. Alternative therapeutic strategies focusing away from arginine may be need for the treatment of this dysfunction.
Sodha
Neel R
NR
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Boodhwani
Munir
M
Clements
Richard T
RT
Feng
Jun
J
Xu
Shu Hua
SH
Sellke
Frank W
FW
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D002908:Chronic Disease; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D005455:Fluorescent Antibody Technique; D016014:Linear Models; D008833:Microcirculation / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001119:Arginase
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