Soluble guanylate cyclase-α1 is required for the cardioprotective effects of inhaled nitric oxide.
Reperfusion injury limits the benefits of revascularization in the treatment of myocardial infarction (MI). Breathing nitric oxide (NO) reduces cardiac ischemia-reperfusion injury in animal models; however, the signaling pathways by which inhaled NO confers cardioprotection remain uncertain. The objective of this study was to learn whether inhaled NO reduces cardiac ischemia-reperfusion injury by activating the cGMP-generating enzyme, soluble guanylate cyclase (sGC), and to investigate whether bone marrow (BM)-derived cells participate in the sGC-mediated cardioprotective effects of inhaled NO. Wild-type (WT) mice and mice deficient in the sGC α(1)-subunit (sGCα(1)(-/-) mice) were subjected to cardiac ischemia for 1 h, followed by 24 h of reperfusion. During ischemia and for the first 10 min of reperfusion, mice were ventilated with oxygen or with oxygen supplemented with NO (80 parts per million). The ratio of MI size to area at risk (MI/AAR) did not differ in WT and sGCα(1)(-/-) mice that did not breathe NO. Breathing NO decreased MI/AAR in WT mice (41%, P = 0.002) but not in sGCα(1)(-/-) mice (7%, P = not significant). BM transplantation was performed to restore WT BM-derived cells to sGCα(1)(-/-) mice. Breathing NO decreased MI/AAR in sGCα(1)(-/-) mice carrying WT BM (39%, P = 0.031). In conclusion, these results demonstrate that a global deficiency of sGCα(1) does not alter the degree of cardiac ischemia-reperfusion injury in mice. The cardioprotective effects of inhaled NO require the presence of sGCα(1). Moreover, our studies suggest that BM-derived cells are key mediators of the ability of NO to reduce cardiac ischemia-reperfusion injury.
Department of Anesthesia, Critical Care, and Pain Medicine, Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA. ynagasaka@partners.org
Yasuko
Y
Nagasaka
Emmanuel S
ES
Buys
Ester
E
Spagnolli
Andrea U
AU
Steinbicker
Sarah R
SR
Hayton
Kristen M
KM
Rauwerdink
Peter
P
Brouckaert
Warren M
WM
Zapol
Kenneth D
KD
Bloch
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
D002316:Cardiotonic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
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