Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy

Abstract

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…However, the sole multicenter study targeting this signaling in HFpEF, the RELAX trial (Effect of Phosphodiesterase‐5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction), reported equivocal results after testing the PDE5 inhibitor sildenafil 47. The results from our study did not completely reproduce the findings of Takimoto et al 6. Although direct comparisons of the studies above are tempting, more importantly these differences provide a reminder that the translation of previous work in rodents to larger mammals and/or humans is not inconsequential and should not be assumed.…”

“…The cGMP‐PKG‐PDE5 signaling axis has been hypothesized to contribute to the pathophysiology of human HF 6, 50, 51, 52. However, this finding is not definitive in a setting of human HFpEF5, 9 where clinical data have failed to show benefits previously reported in multiple animal models 47, 50.…”

“…The differences in cardiac biology between small and large mammals are not purely academic. Originally, work from Takimoto et al6 demonstrated the beneficial effects of PDE5 inhibition showing sildenafil attenuated hypertrophy, decreased fibrosis, and restored LV relaxation kinetics in aortic‐banded mice. Several preclinical and clinical studies followed investigating various methods of preserving cGMP levels, with beneficial results 5, 9, 10, 15, 44, 45, 46.…”

“…Western blot analysis was used to determine protein levels as previously described6, 16, 19, 24 in buffer containing 150 mmol/L NaCl, 10 mmol/L Tris pH 7.4, 1 mmol/L EDTA, 1% Triton X‐100, and protease/phosphatase inhibitors (Halt, Thermo Scientific). After sonication, the lysates were centrifuged at 17 000 g for 10 minutes to remove insoluble material and sample concentration was then determined by Bradford assay (Bio‐Rad).…”

“…Cyclic guanosine monophosphate (cGMP) levels modulate many signaling pathways regulating diastolic function and may inhibit ventricular hypertrophy and stiffness while promoting diastolic relaxation 5, 6, 7, 8. There is growing evidence the cGMP signaling cascade is disturbed in HFpEF patients and could contribute to diastolic dysfunction 4, 5, 9, 10.…”