Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Abstract

The nitrite anion is reduced to nitric oxide (NO • ) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO • signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ( +/+ ) and knockout ( −/− ) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO • generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO • generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO • by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin +/+ but not in myoglobin −/− hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin +/+ mice, whereas in myoglobin −/− mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice

Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotype

“…Another, more controversially discussed role is Mbs' facilitation of O 2 diffusion within muscle cells (Wittenberg, 1970;Jürgens et al, 1994). Although Mb knockout mice exhibited normal exercise capacity and no signs of compromised cardiac energetics due to multiple systemic compensations (Garry et al, 1998;Gödecke et al, 1999), follow-up studies stressed the importance of functional Mb in maintaining nitric oxide (NO) homeostasis in muscle through either scavenging (Flögel et al, 2001) or producing the NO molecule (Hendgen-Cotta et al, 2008). That way, Mb might participate in tuning vasodilatory responsiveness and protecting the respiratory chain from NO inhibition (Brunori, 2001).…”

Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

“…This provides a comparative control where stability of another protein, Mb, is enhanced in cetaceans rather than apes, but stability of SOD1 it is enhanced in great apes. This fits well with the limited role of Mb in primates in terms of oxygen storage, although other functions (such as NO regulation) are notable [87]; in whales, Mb is more important viz. its 10-fold higher concentration and effect on aerobic dive limits [88,89].…”

Monitoring Changes in the Redox State of Myoglobin in Cardiomyocytes by Raman Spectroscopy Enables the Protective Effect of NO Donors to Be Evaluated

“…10 Respiration and cellular viability are regulated under conditions of hypoxia by the reduction of nitrite ions to NO mediated by the heme protein, myoglobin. 11 The oxygenated state of myoglobin also acts as a scavenger of cellular NO and, hence, the protein plays a vital role in NO homeostasis, which is particularly important in cardiomyocytes as elevated levels inhibit mitochondrial respiration. 12,13 Non-resonance 14,15 and resonance [16][17][18][19] Raman spectroscopy have been used before in structural imaging of heart tissue 16 and to monitor dynamic changes in both isolated hearts 18 , cardiomyocytes [14][15][16][17] and exposed mitochondria.…”