Pathophysiological Roles for Local Upregulation of Endothelin-1 in the Heart and Blood Vessels [microform] : Lessons from Mice Overexpressing Conditional and Tissue-specific Transgenes

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Binary transgenic mice with arterial-specific over-expression of human ET-1 [BT: ET+/SM22alpha-tTA+] demonstrated an increase in tail systolic blood pressure at 3 week following DOX withdrawal, associated with an impaired acetylcholine-mediated vasorelaxation, increased collagen deposition, and attenuated ET-1-mediated vasoconstriction, as compared to non-BT or DOX-treated BT. However, the mRNA level of ET-1 in aortae of BT mice at 6 week was decreased compared to those at 3 week following DOX withdrawal. Concomitantly, endothelial function, vasoconstrictor responses to ET-1 and blood pressure in BT mice at 6 week following DOX withdrawal no longer differed from non-BT mice. These data showed that 3 weeks of SM22alpha promoter-defined over-expression of ET-1 is sufficient to cause an increase in blood pressure, but that subsequent reduction of ET-1 over-expression in this model limits the duration of the observed phenotype. Endothelin-1 (ET-1) has been implicated in numerous cardiovascular diseases. While the local expression of ET-1 and its receptors ETA and ETB is increased in many disease states, it is unknown whether up-regulation of the endothelin system is adaptive or pathogenic. To delineate the direct role of ET-1 in the diseased heart and blood vessels independently, we generated transgenic mice with conditional and targeted over-expression of ET-1 in cardiomyocytes and arterial smooth muscle cells, respectively, by employing a tissue-specific tetracycline-regulated gene expression system (Tet-OFF). Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This [ET +] line was bred with one harboring cardiac myocyte-restricted expression of tTA [alphaMHC-tTA] or arterial smooth muscle-restricted expression of tTA [SM22alpha-tTA]. Binary transgenic mice with cardiac-specific over-expression of human ET-1 [BT: ET+/alphaMHC-tTA+] demonstrated progressive mortality between 5--11 weeks after DOX withdrawal, associated with an interstitial inflammatory infiltrate, nuclear NF-kappaB translocation and increased expression of TNF-alpha, IFN-gamma, IL-1 and IL-6. Survival in BT mice was prolonged with the administration of a combined ETA/ET B antagonist but not an ETA-selective antagonist, consistent with a role for ETB in this model. These are the first data to demonstrate that cardiac over-expression of ET-1 is sufficient to induce an inflammatory cascade and dilated cardiomyopathy, leading to heart failure and death.

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