Medicine and Health Sciences
Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat a-myosin heavy chain promoter (a-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these a-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between a-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where a-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, a-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that a-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the a-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the a-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury.
Elsherif, L., Wang, X., Grachoff, M., Wolska, B. M., Geenen, D. L., & O’Bryan, J. P. (2012). Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. PLOS ONE, 7(1). https://doi.org/10.1371/journal.pone.0030129
Elsherif, Laila; Wang, Xuerong; Grachoff, Milana; Wolska, Beata; Geenen, David; and O'Bryan, John, "Cardiac-Specific Expression of the Tetracycline Transactivator Confers Increased Heart Function and Survival Following Ischemia Reperfusion Injury" (2012). Peer Reviewed Articles. 36.