Left ventricular hypertrophy is an adaptive response by the heart to many stresses including hypertension, genetic mutations in cardiac contractile proteins, and mechanical stress. This initially compensatory response may also cause morbidity and mortality secondary to diastolic dysfunction and arrhythmias. Despite the clinical importance of cardiac hypertrophy, the molecular pathways leading to its development are poorly understood. The long-term objectives of this project are to define the regulatory mechanisms involved in cardiac hypertrophy and apply these paradigms to develop therapeutic strategies appropriate for the clinical arena. Previously, others have implicated the serine phosphatase calcineurin and the transcription factor NF-AT3 as central mediators of cardiac hypertrophy. The initial aim of this proposal is to investigate the role of NF-AT3 in cardiac biology by generating mice deficient in NF-AT3. These mice will be characterized using molecular, histological, and cardiac catheterization techniques providing an understanding of NF- AT3 which is necessary prior to designing clinical therapeutic strategies involving this factor. Inhibiting NF-AT3 activity may have untoward effects that may be uncovered by characterizing mice deficient in NF- AT3. Our secondary aim1or this proposal is to identity what role NF- AT3 plays in the hypertrophic response to various stimuli using three separate mouse models: aortic banding, chronic over-exposure to angiotensin II, and a transgenic mouse expressing a constitutively active form of calcineurin. In summary, we hope to better understand the role of NF-AT3 permitting us to target rationally clinical strategies involving its inhibition.
|Murphey, Laine J; Eccles, Wendy K; Williams, Gordon H et al. (2004) Loss of sodium modulation of plasma kinins in human hypertension. J Pharmacol Exp Ther 308:1046-52|