NO/redox disequilibrium in the failing heart and cardiovascular system

Abstract

There is growing evidence that the altered production and/or spatiotemporal distribution of reactive oxygen and nitrogen species creates oxidative and/or nitrosative stresses in the failing heart and vascular tree, which contribute to the abnormal cardiac and vascular phenotypes that characterize the failing cardiovascular system. These derangements at the integrated system level can be interpreted at the cellular and molecular levels in terms of adverse effects on signaling elements in the heart, vasculature, and blood that subserve cardiac and vascular homeostasis.

Figure 1

(A) Spatial localization of NOSs and oxidases in the cardiac myocyte. NOS3 localizes to the sarcolemmal caveolae (85, 97), where it participates in regulation of L-type Ca²⁺ channel (LTCC) currents, mediated either by cGMP formation (S64) or by S-nitrosylation of the LTCC (S13). NOS1 localizes to the SR (32), where it facilitates the SR Ca²⁺ cycle (97) by S-nitrosylation of the RyR and possibly the SR Ca²⁺ ATPase (SERCA2a) (17, 33). XOR also localizes to the SR in the cardiac myocyte; upregulation of protein or activity (caused by SR NOS1 deficiency) disrupts SNO regulation of the RyR (22). Other oxidases (e.g., NADPH oxidase) have been described in the cardiac myocyte (50), but precise signaling roles, identities, and/or subcellular localizations have not been elucidated. The mitochondria are an additional source of both O₂^– and NO, which may participate in control of mitochondrial respiration (S65–S67) and apoptosis (S41). Cyt, cytochrome; PLB, phospholamban. (B) Regulation of the RyR by S-nitrosylation. S-nitrosylation occurs at a single cysteine residue (1 of approximately 50 free thiols), which resides within a calmodulin-binding domain of the cardiac RyR (17). NO binding (shown for RyR1 of skeletal muscle) occurs in an oxygen-concentration–dependent manner and primes the channel for calmodulin regulation (18). Higher pO₂ oxidizes a small set of RyR-associated thiols that regulate the channel’s responsiveness to NO. SH, reduced thiol; S-S, oxidized thiols; CAM, calmodulin; x refers to a small set between 1 and 3.

Figure 2

NO/redox-based signaling and nitrosative stress. Molecular recognition by cysteine-containing proteins is achieved either through the existence of single classes of thiols that are adapted to differentiate NO modification (S-nitrosylation) from oxidations (S-glutathionylation, S-S [intramolecular disulfide] and/or sulfur oxides [SO_x^–, where x is 1–3]) – exemplified in protein 1 – or through the presence of multiple classes of thiols, each adapted to recognize different redox-related molecules, including NO, GSNO, H₂O₂, O₂, and cellular redox potential (for protein 2, note that some classes of thiols may be functionally linked to others, exemplified in the pO₂-dependent oxidation of RyR thiols that promotes S-nitrosylation). In model 1, thiol oxidation would adversely impact nitrosylation signaling. In model 2, signal malfunction may result from altered amounts, timing, and/or the nature of RNS/ROS-based modifications. S, cysteine thiol; GSH/GSSG, glutathione/glutathione disulfide; pO₂, partial pressure of O₂.

Figure 3

Consequences of NO/redox disequilibrium in the cardiovascular system – congestive HF phenotype. The balance between nitric oxide (NOS and hemoglobin–based activities) and superoxide/ROS production (oxidase activity) plays a pivotal role in cell/organ function at key sites in the cardiovascular system, including the heart (A), large- and medium-sized conductance blood vessels (B), and the microvasculature (C) (S12). At each of these sites, NO/redox disequilibrium is identified with dysregulated NO-based signaling. (A) In the cardiac myocyte, NO regulates receptor-mediated signal transduction, the calcium cycle, mitrochondrial respiration, and myofilament contractility. Loss of NOS in the cardiac SR (95) impairs NO signaling and creates oxidative stress (by relieving inhibition of the oxidase) (22). Upregulation of inducible NOS (NOS2) may further disrupt physiologic NO regulation by producing a nitrosative stress. The NO/redox disequilibrium that ensues in HF is characterized by disruption and/or impairment of the cardiac calcium cycle, mitochondrial respiration, and myofilament responsiveness to activator calcium. (B) In conductance vessels, vasoconstriction may result from diminished endothelial NOS activity and/or impaired delivery of plasma-borne NO bioactivity. A NO/redox disequilibrium is linked to increased expression or activity of both vascular NADPH oxidase (Nox4) (99) and circulating XO (46). (C) In the microvasculature, rbcs govern NO bioactivity. Lower venous O₂ saturation in HF may subserve a NO/redox disequilibrium by impairing NO release from rbcs (SNO-Hb) and promoting hemoglobin oxidase activity (44, 75). Impaired vasodilation by rbcs may exacerbate tissue ischemia.