Contemporary Approaches to Modulating the Nitric Oxide-cGMP Pathway in Cardiovascular Disease

Abstract

Endothelial cells lining the vessel wall control important aspects of vascular homeostasis. In particular, the production of endothelium-derived nitric oxide and activation of soluble guanylate cyclase promotes endothelial quiescence and governs vasomotor function and proportional remodeling of blood vessels. Here, we discuss novel approaches to improve endothelial nitric oxide generation and preserve its bioavailability. We also discuss therapeutic opportunities aimed at activation of soluble guanylate cyclase for multiple cardiovascular indications.

Keywords: caveolin-1; endothelial cells; heart failure; nitrates; nitric oxide.

Figure 1. Proteins and enzymes involved in the NO-NOsGC-cGMP pathway and its modulators

Key players of the pathway are shown in blue, whereas the positive modulators are shown in yellow and the negative modulators in purple. Endothelial cells (EC) is shown in green (top), while the vascular smooth muscle cell (VSMC) is shown in red (bottom). The space between the two cells is called myoendothelial junction (MEJ). cGMP mediates its cellular functions through cGMP-modulated (cyclic nucleotide-gated, CNG) cation channels, cGMP-dependent protein kinases (cGKs) and cGMP-regulated phosphodiesterases (PDEs). BH₄, tetrahydrobiopterin; CAV1, caveolin-1; cGMP, cyclic guanosine monophosphate; CYB5R3, NADH-cytochrome b₅ reductase 3; DNA, desoxyribose nucleic acid; eNOS, endothelial nitric oxide synthase (NOS3); NO, nitric oxide; NOsGC, NO-sensitive guanylate cyclase; Hb²⁺/Hb³⁺, hemoglobin α (reduced/oxidized); PDE, phosphodiesterase.

Figure 2. Mechanism of action of cavnoxin and cavtratin

top: A) Physiological conditions: caveolin-1 as part of the caveolae binds eNOS and inhibits its activity through interaction with Phe-92. B) In the presence of cavtratin: cavtratin binds eNOS and inhibits it through the Phe-92 site of the peptide. C) In the presence of cavnoxin: cavnoxin competes with the endogenous caveolin-1 and disinhibits eNOS as the Phe92Ala peptide lacks the ability to inhibit eNOS. bottom: amino acid alignment between CAV1, cavnoxin and cavtratin.

Figure 3. Mechanism of action of NOsGC stimulators and activators

NOsGC stimulators bind to the enzyme and act in an allosteric manner. NO and NOsGC stimulators enhance the NOsGC activity synergistically. NOsGC activators occupy the heme binding site and work therefore only additively with NO. The oxidation of the heme-Fe²⁺ to heme-Fe³⁺ results in a weaker binding of heme to NOsGC, hence allowing the NOsGC activators to occupy the heme binding site easier. The schematic is modified after Zorn and Wells, 2010.