Regulation of cardiac pacemaker activity by PDE4 isoforms – PacePDE
Despite the tremendous progress made in the prevention, diagnosis, and treatment of cardiovascular (CV) diseases, they
continue to cause a large proportion of deaths and disability in Europe, and place a substantial burden on the health care
systems and economies of Europe.
Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and total and
CV morbi-mortality. HR at rest is an important predictor of heart failure and coronary heart disease. Data now suggest that
HR is a treatable risk factor in patients with CV disease, and not simply a prognostic marker. There is increasing evidence
of improved outcomes following the reduction of raised HR. To date, molecules such as ß-blockers and Ca2+ channel
antagonists reduce HR but have multiple additional effects on the CV system and their use may be limited by adverse
reactions or contraindications.
The identification of the cellular and molecular mechanisms specifically involved in the generation and regulation of
cardiac automatism, also called pacemaker activity, is fundamental to understanding the role of rhythm in CV diseases.
The autonomic nervous system is the major extracardiac determinant of the HR. An increase in cyclic AMP (cAMP) levels
following a catecholamine release induces a chronotropic effect. Intracellular cAMP levels result from the balance between
its synthesis by adenylyl cyclases and its degradation by phosphodiesterases (PDEs). PDEs represent the only known
route for degrading the second messenger uniquely positioning them to provide a key regulatory role. Among the 5 PDE
families (PDE1-4 and 8) degrading cAMP in the heart, PDE4 is critical for the regulation of cardiac excitation-contraction
coupling in atrial and ventricular myocytes. The PDE4 family is encoded by 4 genes among which 3 are expressed in the
heart (pde4a, pde4b and pde4d) and encode for multiple variants. Each PDE4 variant plays a unique and non-overlapping
physiological role in the body. However, their respective contribution to the regulation of pacemaker activity remains illdefined.
The overall aim of this project is to define the precise role of the distinct PDE4 isoforms in the control of cardiac
pacemaker activity. Using genetically engineered mice, as well as a combination of molecular and physiological
approaches will allow a unique and global characterization of the functional roles of the various PDE4 isoforms in the
sinoatrial node (origin of pacemaker activity) and will refine our view of PDE participation in the regulation of pacemaker
activity. The characterization of the PDE4 isoforms specifically involved in the control of cardiac automatism is important
for basic science knowledge and has a clinical relevance. Lowering HR represents an important therapeutic approach for
the treatment of heart failure and coronary heart disease. Therefore a selective activation of PDE4, whose expression is
decreased in heart failure, to lower HR would be a promising strategy to treat numerous cardiac diseases.
Madame Delphine Mika (Laboratoire de Signalisation et Physiopathologie Cardiovasculaire)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM UMR-S 1180 Laboratoire de Signalisation et Physiopathologie Cardiovasculaire
Help of the ANR 192,189 euros
Beginning and duration of the scientific project: September 2016 - 24 Months