Heart failure, a condition characterized by the inability of the heart to effectively pump blood as well as by fluid accumulation in the lungs and other tissues, is suffered by an estimated five million Americans and is responsible for 300,000 deaths in the U.S. annually, according to the National Heart, Lung and Blood Institute. It is the single largest Medicare expense, at a cost of $33.2 billion each year. The five-year mortality rate with heart failure can be as high as 50 percent.

Cordex's scientific consultants, Jonathan S. Stamler, M.D., and Joshua M. Hare, M.D., have developed and tested new therapeutic modalities to preserve and improve cardiac function. Cordex has been granted an exclusive, worldwide license from Duke University and Johns Hopkins University to develop and commercialize their portfolio of investigational cardiovascular drugs for the treatment of heart failure.

The most advanced heart failure drug candidate in the portfolio is CDP-1050. The drug is expected to enter a Phase 2 clinical study early in 2009. CDP-1050 is designed to correct nitric oxide and redox imbalance in the failing heart and the cardiovascular system. The drug has a dual mechanism of action; it inhibits the production of tissue-damaging reactive oxygen radicals, and restores nitric oxide to physiologic levels. The principal therapeutic target of the drug is the ryanodine receptor, a key calcium-ion channel in the heart that supplies the calcium necessary for the heart to contract. By improving the redox/nitric oxide balance, CDP-1050 is expected to improve the fucnction of the ryanodine receptor and calcium cycling in the heart. These effects at the sub-celluar level, would be manifested on the organ level in increased efficiency of cardiac contractility.

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). 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 impairs NO signaling and creates oxidative stress (by relieving inhibition of the oxidase). 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) and circulating XO. (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. Impaired vasodilation by RBCs may exacerbate tissue ischemia.

 

Spatial localization of NOSs and oxidases in the cardiac myocyte. NOS3 localizes to the sarcolemmal caveolae, where it participates in regulation of L-type Ca²⁺ channel (LTCC) currents, mediated either by cGMP formation or by S-nitrosylation of the LTCC. NOS1 localizes to the SR, where it facilitates the SR Ca²⁺ cycle by S-nitrosylation of the RyR and possibly the SR Ca²⁺ ATPase (SERCA2a). XOR also localizes to the SR in the cardiac myocyte; upregulation (caused by SR NOS1 deficiency) disrupts NOS regulation of the RyR. Other oxidases (e.g., NADPH oxidase) have been described in the cardiac myocyte, but precise signaling roles, identities, and/or subcellular localizations have not been elucidated. The mitochondria are an additional source of both O_2- and NO, which may participate in control of mitochondrial respiration and apoptosis. Cyt, cytochrome; PLB, phospholamban.

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 [SOx–, 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 reactive nitrogen species/reactive oxygen species-based modifications. S, cysteine thiol; glutathione/oxidized glutathione, glutathione/glutathione disulfide; pO₂, partial pressure of O₂.

 

Hare JM, Stamler JS. NO/redox disequilibrium in the failing heart and cardiovascular system. The Journal of Clinical Investigation. 2005;115: 509-517. Link to Article

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This diagram shows the modulation of the excitation contraction coupling in cardiac myocytes by nitric oxide (NO). Two NO-producing enzymes are depicted: endothelial nNO synthase (eNOS), which is preferentially localized to the caveolae of the cell membrane where it is associated with the structural protein caveolin-3 (Cav-3), and neuronal NO synthase (nNOS), which is preferentially localized in the sarcoplasmic reticulum (SR) where it is associated with the Ca²⁺ channel ryanodine receptor (RyR2) and the enzyme xanthine oxyreductase (XOR). NO produced by nNOS regulates the function of RyR2 by S-nitrosylation, and suppresses the activity of XOR, thereby reducing the production by this enzyme of reactive oxygen species (O_2-). Contraction of cardiac myocytes is initiated by the influx of Ca²⁺ through the L-Type Ca²⁺ channel (LTCC) during the plateau of the action potential, which triggers the release of Ca²⁺ from the SR through the RYR2. The elevated level of Ca²⁺ in the cytoplasm facilitates the contraction of the myofilaments. Ca²⁺ is pumped back into the SR by the SR Ca²⁺ ATPase (SERCA). In heart failure, nNOS partially translocates to the cell membrane resulting in loss of RyR2 regulation and increased production of O_2-,which makes RYR2 leaky. Sustained elevated cytoplasmic level of Ca²⁺ (calcium overload) decreases the myofilament Ca²⁺-sensitivity resulting in poor myocardial contractility, a characteristic of the failing heart. Calcium overload can lead also to lethal cardiac arrhythmias.

 

NCX: Na⁺- Ca²⁺ Exchanger (a Na⁺- gradient-dependent transporter that can function in a direct or reverse mode; i.e., it can pump Ca²⁺ into or out of the cell); PLB: phospholamban (a protein that regulates SERCA); PMCA: plasmalemma (cell membrane) Ca²⁺ ATPase; T-tubule: transverse tubule (invaginations of the cell membrane)

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. NO binding (shown for RyR1 of skeletal muscle) occurs in an oxygen-concentration– dependent manner and primes the channel for calmodulin regulation. 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.