Urotensin II-Mediated Cardiac Hypertrophic Gene Induction Requires Cam Kinase Kinase




Valencia, Thomas G.


Journal Title

Journal ISSN

Volume Title



Thomas G. Valencia, Urotensin II-mediated cardiac hypertrophic gene induction requires CaM kinase kinase. Doctor of Philosophy (Biomedical Sciences), December 2006, 191 pp, 2 tables, 42 illustrations, references, 163 titles. Cardiac hypertrophy arises from various forms of physical stress that result in an increased workload and decreased cardiac output. Therefore, cardiac hypertrophy is the common compensatory mechanism employed by the heart to maintain a normal cardiac output. Gq-coupled receptors such as the angiotensin II receptor (AngIIR) and the endothelin-1 receptor (ET-1R) are capable of activating the CaMK and MAPK cascades and are involved in cardiac hypertrophy. Mechanical stress has been shown to result in the release of both AngII and ET-1 from the heart leading to an autocrine stimulation of myocyte hypertrophy. The Urotensin II receptor (UIIR) is coupled to Gq and is expressed in the healthy adult heart at low levels and becomes over-expressed under pathological conditions that leads to hypertrophy. UII is capable of inducing hypertrophy in cardiomyoctyes only when sufficient receptor is expressed. In this study, the mechanism by which UII becomes expressed was examined as was the mechanisms through which UII induces hypertrophy of cardiomyocytes. Data described in this dissertation demonstrated of UIIR message and protein. UII was able to stimulate the promoter activity of ANF and SkA and the transcriptional activity of MEF2 in a CaMKK-dependent manner. UII stimulation of ANF, BNP, βMHC and SkA gene expression was dependent on CaMKK. UII stimulation caused the CaMKK-dependent activation of CaMKI. CaMKI completely rescued UII stimulation of ANF and SkA promoter activities as well as MEF2 activity with CaMKK pharmacologically inhibited. We demonstrated that the UII-induced activation of p38 and ERK1/2 MAP kinases was dependent on CaMKK suggesting a novel cross-talk mechanism not previously described in cardiomyoctyes. Both UII- and CaMKI-mediated induction of ANF, SkA and MEF2 reporter activities was dependent on p38 and ERK1/2. Taken together, these data identify CaMKK as a central mediator in Gq activation of hypertrophy by UII.