In most tissues, cyclic nucleotides (cAMP and cGMP) act as second messengers to mediate the effects of physiologic and pharmacologic agents. In the cardiovascular system, both cAMP and cGMP are involved in regulating cardiac muscle and vascular smooth muscle contractility and growth. Unregulated cardiac and vascular muscle contractility or growth are involved in many cardiovascular diseases (congestive heart failure, hypertension, stroke and atherosclerosis).
Studies in progress in this laboratory focus on the molecular basis of cyclic nucleotide-mediated effects in vascular tissues. More specifically, we study the enzymes that synthesise cAMP and cGMP (adenylyl cyclase and guanylyl cyclase) and those which catabolically inactivate these two second messengers (cyclic nucleotide phosphodiesterases) using two parallel and complementary approaches. Firstly, cloning of these enzymes from heart and aorta, and expression of the recombinant enzymes, allows for detailed analysis of the structure, function, level of expression and relative abundance of these enzymes in these tissues. Secondly, we are studying cAMP and cGMP metabolism in cultured vascular smooth muscle and vascular endothelial cell systems. With these culture systems, the control of the level of the cyclic nucleotides by the endogenous enzymes or by transiently expressed recombinant enzymes and the resultant effect on cell growth and differentiation can be assessed. Combined, these approaches allow us to study nucleotide-mediated signalling both at a molecular as well as a cellular level.