Soluble guanylate cyclase-α₁is required for the cardioprotective effects of inhaled nitric oxide

Abstract

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.

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…In myocardial injury, inhaled gaseous NO inhibited cardiomyocyte apoptosis and reduced infarct size [122-125]. The concentration of creatine kinase also decreased [122-124, 126, 127]. Increasing NO mediated respiratory complexes, leading to improved myocardial oxygen consumption and reduced production of superoxide.…”

IRAG and novel PKG targeting in the cardiovascular system

“…Hence, the modulation of NO/cGMP signaling is an important pharmacological target pathway for the prevention of cardiovascular diseases such as angina pectoris, hypertension, heart insufficiency, and atherosclerosis (7,57,62). The knowledge of the details regarding NO/cGMP signal transduction is essential for the understanding of the physiological and pathophysiological regulation and the modulation at diverse steps in this signaling pathway (Fig.…”

Preventing Ischemic Brain Injury after Sudden Cardiac Arrest Using NO Inhalation

“…We previously reported that neutrophils are required for inhaled NO to reduce MI size in wild-type (WT) mice subjected to transient left coronary artery occlusion [40]. Along these lines, we recently observed that NO breathing markedly decreased MI size in WT but not in sGCα1 -/-mice [50]. Furthermore, breathing NO decreased MI size in chimeric sGCα1…”