The emperor's new clothes: PDE5 and the heart

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Pharmacology

Background:

• Phosphodiesterase-5 (PDE5) expression in the heart is debated, yet it's hypothesized to regulate cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) signaling.
• PKG activation may mitigate cardiac hypertrophy and adverse remodeling in heart failure.
• The RELAX trial's negative results in heart failure with preserved ejection fraction (HFpEF) underscore the controversy surrounding PDE5's role in the heart.

Purpose of the Study:

• To rigorously investigate the presence and expression levels of PDE5 in cardiac tissue from various species, including humans.
• To determine if PDE5 is expressed in healthy and failing hearts, and if its expression changes with cardiac disease models.
• To assess the potential of PDE5 as a therapeutic target for cardiac hypertrophy and heart failure.

Main Methods:

• Utilized one- and two-dimensional electrophoresis and Western blotting techniques.
• Examined cardiac tissue from mice (pre- and post-trans-aortic constriction), dogs (control and HFpEF models), and human hearts (healthy and failing).
• Employed lung tissue samples as positive controls for PDE5 detection.

Main Results:

• PDE5 was undetectable in all examined cardiac tissue lysates, including human, mouse, and dog hearts.
• PDE5 was successfully detected in positive control lung samples, confirming assay validity.
• The absence of detectable PDE5 in cardiac tissue suggests minimal or no expression in the myocardium.

Conclusions:

• PDE5 is likely absent or present in negligible amounts in cardiac muscle.
• PDE5 is unlikely to be significantly involved in regulating cGMP-PKG signaling within cardiomyocytes.
• PDE5 does not represent a suitable drug target for treating cardiac hypertrophy or heart failure.