(Verbatim from the application): Hypertrophic heart disease is an important clinical problem producing substantial morbidity, mortality and health care expense. The peptide endothelin-1 (ET-1) is one of the signals for the development of cardiac hypertrophy. In order to examine the likely autocrine/paracrine role of endogenous cardiomyocyte endothelin in hypertrophy we have chosen a genetic approach to eliminate the endothelin-1 gene from the hearts of transgenic mice. However, a traditional knockout of the endothelin gene produces pharyngeal hypoplasia, which leads to suffocation shortly after birth, and prevents evaluation of the physiological effects of the mutation in adult mice. We have therefore created a cardiac specific knockout of the endothelin gene to test our central hypothesis that ET-1 acts as a paracrine facilitator of diverse hypertrophic stimuli. We have three specific aims: 1) To determine the hypertrophic and contractile response of the ET-1 deficient heart in specific models of hypertrophy. 2) To identify the genes that are transcriptionally regulated by ET-1 signaling in the setting of these models of hypertrophy. 3) To determine the effect of ET-1 ablation on the response of the CNA, CamK4 and MAPK dependent hypertrophic pathways. Methods will include: 1) Cardiac specific deletion of ET-1 by breeding of mice containing Cre recombinase under the regulation of the cardiac specific alpha-myosin heavy chain promoter and a lox-bracketed endothelin-1 gene. 2) Stimulation of hypertrophy with exogenous thyroid, isoproterenol and angiotensin infusion. 3) Measurement of hypertrophic response by: a. Expression of genes involved in myocardiocyte growth (Northern and RT-PCE techniques), b. a broad evaluation of transcriptional response (microarray analysis), and c. anatomic remodeling and ventricular performance (MRI imaging). 4) Enzyme assays of the activity of CNA, CamK4 and MAPKs in hearts of ET-1 deleted and wild-type mice subjected to hypertrophic stimuli.
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