Impact of mitochondrial nitrite reductase on hemodynamics and myocardial contractility

Abstract

Inorganic nitrite (NO2 −) can be reduced back to nitric oxide (NO) by several heme proteins called nitrite reductases (NR) which affect both the vascular tonus and hemodynamics. The objective of this study was to clarify the impact of several NRs on the regulation of hemodynamics, for which hemodynamic parameters such as heart rate, blood pressure, arterial stiffness, peripheral resistance and myocardial contractility were characterized by pulse wave analysis. We have demonstrated that NO2 − reduced to NO in RBCs predominantly influences the heart rate, while myoglobin (Mb) and mitochondria-derived NO regulates arterial stiffness, peripheral resistance and myocardial contractility. Using ex vivo on-line NO-detection, we showed that Mb is the strongest NR occurring in heart, which operates sufficiently only at very low oxygen levels. In contrast, mitochondrial NR operates under both hypoxia and normoxia. Additional experiments with cardiomyocytes suggested that only mitochondria-derived generation of NO regulates cGMP levels mediating the contractility of cardiomyocytes. Our data suggest that a network of NRs is involved in NO2 − mediated regulation of hemodynamics. Oxygen tension and hematocrit define the activity of specific NRs.

A Ratiometric Acoustogenic Probe for in Vivo Imaging of Endogenous Nitric Oxide

“…1 H NMR (500 MHz, CDCl 3 ) δ 7.45 (dd, J = 8.3, 1.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.27−7.16 (m, 6H), 6.40 (d, J = 8.3 Hz, 1H), 4.82 (s, 1H), 4.78 (dd, J = 12.5, 6.3 Hz, 1H), 4.60 (dd, J = 12.5, 8.5 Hz, 1H), 4.13 (tt, J = 8.3, 6.1 Hz, 1H), 3.79 (s, 3H), 3.30 (dd, J = 16.9, 6.2 Hz, 1H), 3.23 (dd, J = 16.9, 8.0 Hz, 1H), 2.85 (s, 3H). 13 (Z)-2-Methoxy-N-methyl-4-(4-phenyl-5-((3-phenyl-5-(4-(prop-2-yn-1-yloxy)phenyl)-2H-pyrrol-2-ylidene)amino)-1Hpyrrol-2-yl)aniline (7). A suspension of 6 (0.40 g, 1.2 mmol, 1 equiv) and 35 (0.80 g, 2.5 mmol, 2 equiv) in n-butanol (25 mL) was heated to 110 °C to dissolve all solids.…”

“…The NOS family includes an inducible, calcium-independent isoform (iNOS), which is primarily linked to the immune response, and constitutively expressed, calcium-dependent isoforms (ncNOS and ecNOS), which are linked to homeostatic maintenance. 6 NO can also be enzymatically 7 or nonenzymatically generated by the reduction of nitrite under hypoxic conditions, a process which has been observed in the ischemic heart and results in NO-mediated tissue damage. 8 Due to its various roles in physiological and pathological processes, the identification, detection, and quantification of NO continues to be an active area of research.…”

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

“…Moreover, nitrite can be reconverted to NO [17] by mitochondrial nitrite reductase in relation to hypoxia [18]. These NO pathways in interaction with Hb are mainly involved in hypoxia-induced vasodilation [18], but not in physiological shear endothelium-dependent vasodilation in which the inhibitory role of free Hb and nitrate formation predominates. Moreover, cytoglobin (Cygb), an ancient hemoglobin isoform, plays also a major role in the modulation of NO activity [19].…”

Catalase-Like Antioxidant Activity is Unaltered in Hypochlorous Acid Oxidized Horse Heart Myoglobin

“…In the case of NO, Mb can diminish the concentration of this vasoactive molecule through oxidation [10,11] and/or increase NO concentrating through Mb’s inherent nitrite reductase activity [12]. In particular, the ability of Mb to act as a nitrite reductase has been linked to regulation of muscle contractile function [13]. Furthermore, cardiac Mb is also a pseudo-peroxidase that also exhibits a catalase-like antioxidant activity [14]; both enzymic activities may be important in regulating levels of cardiac hydrogen peroxide (H 2 O 2 ) particularly following acute ischemia-reperfusion injury post AMI.…”