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Vol. 58, Issue 2, 247-252, August 2000
Department of Pharmacology & Toxicology (D.P., D.H.M.) and
Department of Pathology (D.H.M.), Queen's University, Kingston,
Ontario, Canada
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of
enzymes whose physiological role is the attenuation of the signaling
mediated by the ubiquitous second messengers cAMP and cGMP. Given the
myriad of physiological processes regulated by cAMP and cGMP, PDEs have
long been studied as potential therapeutic targets. Although
phosphodiesterase 3 (PDE3) activity is abundant in human cardiovascular
tissues, and acute PDE3 inhibition, with agents such as milrinone, was
beneficial in heart failure patients, prolonged treatments were
associated with time-dependent reductions in hemodynamic effects and
increased mortality. The molecular basis of this time-dependent
reduction in efficacy has not been elucidated. In this context, we used
a combination of approaches to determine PDE3 expression in human
cardiovascular tissues and to elucidate the effects of prolonged
elevations of cellular cAMP, as would occur with PDE3 inhibition, on
this activity. Although our data confirms the expression of PDE3A in
human blood vessel smooth muscle cells (HASMCs), we identify a
previously unrecognized role for PDE3B in cAMP hydrolysis in human
cardiovascular tissues. Specifically, although both PDE3A and PDE3B
were expressed in HASMCs, their subcellular expression pattern and
regulated expression by cAMP were distinct, with only expression of
PDE3B being subject to cAMP-regulated expression. Thus, a paradigm
emerges that allows for dual expression, with distinctive regulation,
of both PDE3A and PDE3B proteins in cardiovascular tissues that may
have profound significance for the rational design of molecules
regulating this PDE activity.
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