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Updated: Jun 6, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Conserved expression and functions of PDE4 in rodent and human heart
Wito Richter1, Moses Xie, Colleen Scheitrum
1Department of Gynecology, Obstetrics, and Reproductive Sciences, Center for Reproductive Sciences, University of California San Francisco, Box 0556, 513 Parnassus Avenue, San Francisco, CA 94143-0556, USA. richterw@obgyn.ucsf.edu
Abstract:
PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation-contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has 'global' effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts.
Insights
Phosphodiesterase 4 (PDE4) enzymes regulate heart cell signaling similarly in rodents and humans. However, PDE4 inhibition has broader effects in rodent hearts due to higher overall phosphodiesterase activity in human hearts.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
- Biochemistry
Background:
- Phosphodiesterase 4 (PDE4) isoenzymes are crucial for regulating cyclic adenosine monophosphate (cAMP) signaling in cardiac myocytes.
- PDE4 dysfunction is linked to heart failure development in rodents, but its role in human hearts is less understood.
Purpose of the Study:
- To compare the expression and function of PDE4 in rodent and human cardiac cells.
- To investigate species-specific differences in PDE4's role in cAMP signaling and its response to inhibition.
Main Methods:
- Comparative analysis of PDE4 expression, activity, and subcellular localization in rodent and human heart tissue.
- Assessment of PDE4 inhibition effects on protein phosphorylation in cardiomyocytes from both species.
Main Results:
- Similar PDE4 subtypes, splicing variants, and subcellular localization were found in both rodent and human hearts.
- Human hearts exhibit significantly higher non-PDE4 phosphodiesterase activity compared to rodent hearts.
- PDE4 inhibition broadly impacts cAMP signaling in rodents, but elicits a more restricted response in humans.
Conclusions:
- PDE4 enzymes play a conserved role in local cAMP regulation in both rodent and human hearts.
- Differences in total phosphodiesterase activity contribute to distinct cellular responses to PDE4 inhibition between species.
- These findings highlight potential species-specific pharmacological effects of PDE4 inhibitors in cardiovascular conditions.
