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Sustained preconditioning induced by cardiac transgenesis with the tetracycline transactivator

Departments of ¹Radiology and ²Medicine and the ³Cardiovascular Research Institute and ⁴Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California; and the ⁵Veterans Affairs Medical Center, San Francisco, California

Submitted 11 July 2005 ; accepted in final form 13 October 2005

Preconditioning protocols that protect the heart from ischemic injury may aid in the development of new therapies. However, the temporal window of cardioprotection is limited to a few days after the preconditioning stimulus. Here we report a sustained cardioprotected phenotype in mice expressing a tetracycline transactivator (tTA) transcription factor under the control of the -myosin heavy chain (MHC) promoter. MHC-tTA mice were originally designed for tetracycline-regulated gene expression in the heart (Tet system). However, we found that after 45 min of global ischemia at 37°C, left ventricular developed pressure (LVDP) of Langendorff-perfused MHC-tTA mouse hearts rapidly recovered in 5 min to 60% of initial levels, whereas LVDP of wild-type (WT) littermates recovered to only 10% of the initial level. Improved postischemic recovery of function for MHC-tTA hearts was associated with a 50% decrease of infarct size and a significantly smaller release of lactate dehydrogenase to the coronary effluent. Improved postischemic recovery was not attributable to differences in coronary flow that was similar for WT- and MHC-tTA hearts during recovery. Moreover, improved postischemic recovery of MHC-tTA hearts was not abolished by inhibitors of classical cardioprotective effectors (mitochondrial ATP-sensitive K⁺ channels, PKC, or adenosine receptors), suggesting a novel mechanism. Finally, the tetracycline analog doxycycline, which inhibits binding of tTA to DNA, did not abolish improved recovery for MHC-tTA hearts. The sustained cardioprotected phenotype of MHC-tTA hearts may have implications for developing new therapies to minimize cardiac ischemic injury. Furthermore, investigations of cardioprotection using the Tet system may be aberrantly influenced by sustained preconditioning induced by cardiac transgenesis with tTA.

tetracycline-regulated gene expression system; Langendorff; mouse; contraction; cardioprotection; -myosin heavy chain

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