Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

Serine elastases degrade elastin, stimulate vascular smooth muscle cell mig ration and proliferation, and are associated with myocardial damage. To eva luate the impact of elastase inhibition on cardiovascular development and d isease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular sys tem. To distinguish the transgene from endogenous elafin, constructs were m ade incorporating a FLAG sequence, the COOH-terminus FLAG-tagged elafin con struct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant ela fin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but no r in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. Howeve r, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compar ed with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory da mage. Thus, elafin expression may confer a protective advantage in myocardi tis and other inflammatory diseases.