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Review
. 2013 Dec 11;2(6):e000536.
doi: 10.1161/JAHA.113.000536.

The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction

Stephen J Greene  1 , Mihai Gheorghiade, Barry A Borlaug, Burkert Pieske, Muthiah Vaduganathan, John C Burnett Jr, Lothar Roessig, Johannes-Peter Stasch, Scott D Solomon, Walter J Paulus, Javed Butler
Affiliations
Review

The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction

Stephen J Greene et al. J Am Heart Assoc. .
No abstract available

Keywords: cGMP; heart failure; phosphodiesterase 5; preserved ejection fraction; soluble guanylate cyclase.

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Figures

Figure 1.
Figure 1.
cGMP signaling pathways. cGMP is the second messenger of 2 distinct signaling pathways: (1) NO is produced by endothelial cells and binds to sGC in the target cell; and (2) ANP and BNP, derived primarily from cardiomyocytes, stimulate GC‐A, whereas CNP, secreted by endothelial cells, stimulates GC‐B. cGMP signaling may be augmented by (1) the use of NO mimetics such as nitrovasodilators; (2) sGC activators or stimulators; (3) increasing levels of natriuretic peptides; (4) by inhibiting natriuretic peptide degrading enzymes; and (5) inhibiting the activity of cGMP‐hydrolyzing PDEs. ANP indicates atrial natriuretic peptide; BNP, B‐type natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNP, C‐type natriuretic peptide; DPP4, dipeptidyl peptidase IV; GC, guanylate cyclase; GMP, guanosine monophosphate; NEP, neutral endopeptidase; NO, nitric oxide; PDE, phosphodiesterase; PKG, protein kinase G; RA, natriuretic peptide receptor A; sGC, soluble guanylate cyclase. Adapted with permission from Boerrigter et al.
Figure 2.
Figure 2.
cGMP signaling and myocardial dysfunction and remodeling in HFpEF. Comorbidities induce a systemic proinflammatory state with elevated plasma levels of interleukin (IL)–6, tumor necrosis factor (TNF)–α, soluble ST2 (sST2), and pentraxin 3. Coronary microvascular endothelial cells reactively produce reactive oxygen species (ROS), vascular cell adhesion molecules (VCAMs), and E‐selectin. Production of ROS leads to formation of peroxynitrite (ONOO−) and reduced nitric oxide (NO) bioavailability, both of which lower soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes. Lower sGC activity decreases cyclic guanosine monophosphate concentration and protein kinase G (PKG) activity. Low PKG activity increases resting tension (Fpassive) of cardiomyocytes because of hypophosphorylation of titin and removes the brake on prohypertrophic stimuli inducing cardiomyocyte hypertrophy. VCAM and E‐selectin expression in endothelial cells favors migration into the subendothelium of monocytes. These monocytes release transforming growth factor β (TGF‐β). The latter stimulates conversion of fibroblasts to myofibroblasts, which deposit collagen in the interstitial space. cGMP indicates cyclic guanosine monophosphate; COPD, chronic obstructive pulmonary disease; HFpEF, heart failure with preserved ejection fraction. Adapted and modified with permission from Paulus and Tschope.
Figure 3.
Figure 3.
PKG activity and cGMP concentration in myocardial tissue from patients with heart failure with reduced and preserved ejection fraction and aortic stenosis. AS indicates aortic stenosis; cGMP, cyclic guanosine monophosphate; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; PKG, protein kinase G. Adapted and modified with permission from van Heerebeek et al.
Figure 4.
Figure 4.
Schematic representation of the mechanism(s) by which NO‐independent sGC stimulators and sGC activators fit into the NO/sGC/cGMP pathway. Oxidative stress—a risk factor for several cardiovascular diseases—is associated with increased formation of reactive oxygen species that are known to oxidize and inactivate many biomolecules, culminating in tissue damage. In particular, ONOO− oxidizes sGC, resulting in loss of the heme group. Heme‐free sGC is unable to respond to NO and can be regarded as a dysfunctional form of the enzyme (NO stimulates only the native form of sGC). Stimulators of sGC have a dual mode of action: they directly stimulate the native form of the enzyme and make it more sensitive to endogenous NO. Activators of sGC specifically activate dysfunctional or heme‐free sGC. Stimulation of native sGC and activation of heme‐free sGC both lead to increased formation of cGMP, which exerts a profound, multifaceted cytoprotective effect. cGMP indicates cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; NOS, nitric oxide synthase; ONOO−, peroxynitrite; PDE, phosphodiesterase; sGC, soluble guanylate cyclase. Adapted and modified with permission from Hobbs and Stasch.
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