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Cardiovascular Implications in the Use of PDE5 Inhibitor Therapy

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Cardiovascular Implications in the Use of PDE5 Inhibitor Therapy International Journal of Impotence Research (2004) 16, S20–S23 & 2004 Nature Publishing Group All rights reserved 0955-9930/04 $30.00 www.nature.com/ijir Cardiovascular implications in the use of PDE5 inhibitor therapy DH Maurice* Department of Pharmacology & Toxicology, Queen’s University at Kingston, Kingston, ON, Canada Cardiovascular smooth muscle cells (SMCs) exist as resting or activated cells. Resting SMCs produce contractile proteins and are nearly transcriptionally inactive; activated SMCs are transcriptionally active and are involved in pathological processes such as atherosclerosis. Soluble guanylate cyclase, protein kinase G, and protein kinase A are present in SMCs, but their levels can be decreased in activated cells. Phosphodiesterase 3 (PDE3) activity is abundant in cardiovascular tissues; both PDE3A and PDE3B are involved in cyclic adenosine monophosphate (cAMP) hydrolysis in these tissues. Cyclic-AMP-hydrolyzing PDE activities are altered during the phenotypic transition of SMCs from the resting to the activated phenotype. Similar changes have been observed in cyclic guanosine monophosphate cGMP-hydrolyzing PDEs, although the impact of these alterations on PDE5 inhibitor-mediated effects requires further study. This report presents the changes in PDE expression that accompany phenotypic modulation of SMCs and discusses the potential impact of these events on PDE5-mediated cell functions. International Journal of Impotence Research (2004) 16, S20–S23. doi:10.1038/sj.ijir.3901210 Keywords: phosphodiesterase; smooth muscle cells; cyclic AMP; cyclic GMP; protein kinase Introduction Quiescent/resting SMCs, normally present in healthy blood vessels that perfuse most organs, contract and relax in response to pulsatile differ- In addition to physiologically based differences in ences in the blood flow and in response to the the expression of individual phosphodiesterases pharmacologic and physiologic stimuli. This re- (PDEs) in the cells of cardiovascular tissues, the sponse controls the diameter of blood vessels and, as overall cardiovascular health status of patient such, plays an important role in regulating systemic populations also may impact significantly on both blood pressure. Quiescent/resting SMCs express the the types and levels of individual PDEs in these contractile proteins required for the generation of tissues. At present, it is unclear if these differences contractile forces but are, for the most part, affect pharmacologic agents aimed at PDEs or other transcriptionally inactive and display a very low enzymes involved in regulating cyclic nucleotide rate of proliferation and of directed migration. In levels in these cells. contrast, activated/synthetic SMCs are transcrip- This article reviews the current state of knowledge tionally active and exhibit high levels of prolifera- concerning (a) expression of PDEs in cells of the tion and directed migration. Such cells are typically cardiovascular system, (b) changes in PDE expres- involved in processes related to initial establish- sion under certain pathophysiological situations, ment of cardiovascular structures (vasculogenesis) and (c) the potential implications of altered PDE or in the process of neovascularization often expression on the effects of PDE5 inhibitors. More associated with vascularization of newly formed specifically, the regulated expression of PDEs in two tissues in health or disease (angiogenesis). Indeed, distinct phenotypes of smooth muscle cells (SMCs) activated/synthetic SMCs are present during the (quiescent/resting and activated/synthetic) will be development of the cardiovascular system, accumu- described. late in atherosclerotic plaques, and can proliferate and migrate to repopulate the lumen of diseased arteries after successful balloon angioplasty. The two cyclic nucleotides, cyclic adenosine *Correspondence: DH Maurice, PhD, Department of monophosphate (cAMP) and cyclic guanosine Pharmacology & Toxicology, Botterell Hall, A221, Queen’s monophosphate (cGMP), participate in the regulated University at Kingston, Kingston, ON, Canada K7L 3N6. functioning of SMCs of each phenotype. Interest- E-mail: [email protected] ingly, levels of some of the enzymes involved in PDE5 inhibitor cardiovascular effects DH Maurice S21 the synthesis of the cyclic nucleotides in SMCs calcium-calmodulin-regulated PDE1 family en- (eg, soluble guanylyl cyclase) or the effects of the zymes, and PDE5, a cGMP-specific PDE that repre- cyclic nucleotides in cells (e.g., protein kinase G sents the target of agents used in the treatment of (PKG), protein kinase A (PKA)) vary in SMCs of erectile dysfunction (sildenafil, vardenafil and tada- differing phenotypes. Indeed, activated/synthetic lafil), all hydrolyze SMC cGMP. PDE1A and PDE1B SMCs generated by the culturing of quiescent are differentially expressed in SMCs of differing arterial SMCs, or in situ as a result of vascular phenotypes. The species from which the SMCs are damage, demonstrate markedly lower levels of isolated also impact the relative amounts of each several enzymes involved in mediating cGMP PDE1 isoform. effects than are found in quiescent/resting SMCs. In humans, quiescent/resting SMCs express both Recent work from several laboratories has begun to PDE1A and PDE1B, while activated/synthetic SMCs elucidate differences in PDE expression in SMCs express only PDE1A.6 At present, most data are under various conditions. In this context, variants of consistent with levels of PDE5 expression being the PDE3 and PDE4 families play important roles in unaltered between quiescent and activated SMCs. the hydrolysis of cAMP in SMCs. While both However, given the potential importance of changes quiescent/resting and activated/synthetic SMCs each in PDE5 expression during phenotypic modulations, express both PDE3 gene products (PDE3A and and the impact of such differences on PDE5 PDE3B),1,2 levels of PDE3-based cAMP hydrolysis, inhibitor-mediated regulation of SMC function, a and of PDE3A protein expression, is substantially thorough and detailed analysis of this issue in lower in activated/synthetic SMCs than in quies- human SMCs is needed. cent/resting SMCs.3 In contrast to PDE3, levels of In addition to the phenotype-based difference in PDE4 activity and of PDE4D expression are similar in PDE activity and expression in SMCs, the subcel- quiescent/resting and activated/synthetic SMCs. lular expression pattern of these enzymes and their One of the most interesting modes of regulating regulated expression by various signaling systems PDE3 involves the binding of cGMP to the catalytic also differ. For example, while PDE3A and domain of these enzymes, thereby causing compe- PDE3B are each expressed in SMCs, PDE3A alone titive inhibition of cAMP hydrolysis by these is found in cytosolic fractions, while both the enzymes. This inhibitory effect of cGMP on cAMP PDE3A and PDE3B are expressed in particulate hydrolysis accounts for findings that nitric oxide fractions of these cells. Although phosphorylation (NO)-releasing vasodilators increased platelet and by PKA activates both the PDE3 variants, only SMC cAMP, and that these agents synergistically PDE3B levels increase following prolonged eleva- raised cAMP when used in combination with tions in cellular cAMP.2 activators of adenylyl cyclase, such as prostaglandin Similarly, PDE4D activity and expression increase 4,5 E1 or isoproterenol. subsequent to elevated cAMP levels in both quies- Phosphodiesterase 1C (PDE1C), a calcium–calmo- cent/resting and activated/synthetic SMCs, although dulin regulated enzyme that hydrolyzes both cAMP the different PDE4D variants involved are pheno- and cGMP, is also expressed in human SMCs in type dependent. Thus, although quiescent/resting a phenotype-dependent manner. Indeed, while SMCs increase PDE4 activity through the PKA- PDE1C is not expressed in human quiescent/resting dependent phosphorylation and increase expression SMCs, expression of PDE1C is markedly induced of the endogenously expressed PDE4D variant in activated/synthetic human SMCs. High levels of (PDE4D3), activated/synthetic SMCs respond by PDE1C expression were observed in primary cul- activating PDE4D3 and by inducing the expression tures of SMCs derived from explants of human of two PDE4D variants not expressed in SMCs prior newborn and adult aortas, and in SMCs cultured to such treatments (PDE4D1 and PDE4D2).8 from severe atherosclerotic lesions.6 PDE 1C repre- Chronic in vivo exposure to the NO-releasing sented the major cAMP hydrolytic activity in these vasodilator, nitroglycerin, induces expression of SMCs. Since inhibition of PDE1C leads to the Ca2 þ /calmodulin-stimulated PDE1A1, which pre- suppression of human SMC proliferation, PDE1C ferentially degrades cGMP in the rat aorta. Rats expression may serve as a useful marker of human made tolerant to nitroglycerin by continuous infu- SMCs proliferation,7 and PDE1C inhibitors may sion for 3 days showed an increase in Ca2 þ / target proliferating SMCs in relevant situations such calmodulin-stimulated PDE1A1 and a 2.3-fold in- as atherosclerosis. crease in PDE1A1 in their aortas.9 Selective inhibi- In conclusion, enzymes of the PDE1, PDE3 and tion of PDE1 partially restored the sensitivity of PDE4 families of PDE enzymes participate in the tolerant vessels to subsequent nitroglycerin expo- hydrolysis of cAMP in SMCs, and the species from sure. This suggests that increased PDE1A1 activity which these cells are isolated and their phenotypes can decrease cGMP levels and that this mechanism will
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