Hemizygous bi-transgenic tTA+/hPMCA4b mice are viable and fertile and harbor two transgenes using the Tet-Off system. The tTA transgene uses a rat &#945-MHC (Myh6 - myosin, heavy polypeptide 6, cardiac muscle, alpha) promoter directing expression of the transcriptional transactivator (tTA) to cardiomyocytes. The hPMCA4b transgene has ATP2B4 cDNA linked to a bi-directional viral CMV promoter containing Tet Operator sites. lacZ cDNA is present on the other side of the bi-directional CMV promoter. X-gal staining and immunohistochemistry confirm the presence of nuclear-localized lacZ in cardiomyocytes. RT-PCR confirms expression of ATP2B4 in heart, but not in liver, kidney, lung, brain intestine, muscle or aorta or in DOX-treated littermates. ATP2B4 is involved in intracellular calcium homeostasis; heart failure is associated with reduced expression of plasma membrane ATP2B4. In the absence of tetracycline (or its analog doxycycline (dox)), the promoter limits hPMCA4b protein expression to cardiomyocytes. Overexpression results in elevated blood pressure, increased cardiac contractility and lusitropy (rate of myocardial relaxation), as well as an inhibition of cardiac NOS and nNOS-specific activities. Prolonged mild cardiac hypertrophy does not result in cardiac dysfunction. Following myocardial ischemia reperfusion injury (IRI), PMCA4b overexpression preserves cardiac function, limiting infarct progression, cardiac hypertrophy and heart failure (HF). Because this binary transgenic system also allows for a second level of control (i.e., addition of dox), expression of the hPMCA4b protein can be completely abolished; reversing the phenotype.

 tTA+/hPMCA4b bi-transgenic mice allow targeted overexpression or Tet-Off conditional expression of human ATP2B4 (or PMCA4b) in cardiomyocytes. Overexpression of ATP2B4 has a cardioprotective effect following ischemic injury. These mice are suitable for use in applications related to the study of heart failure.

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