Gene therapy can strengthen the heart _ but so far only in transgenicmice.An experiment reported in Friday's Science (April 22) concluded,"This study demonstrates the potential of genetic engineering as amodality for enhancing myocardial and ventricular function . . . invivo." Duke University's Robert Lefkowitz led a nine-author team ofresearchers, whose paper is titled: "Enhanced Myocardial Function inTransgenic Mice Overexpressing the b2-Adrenergic Receptor."In chronic human heart failure, the cardiac muscle's contraction isweakened by loss of b2-adrenergic receptors (b-AR). These cellulargate-keeping proteins admit the epinephrine hormone (a.k.a.adrenaline), which activates the heart's blood-pumping action.The Duke investigators introduced genes for b-AR into the pronuclei ofone-cell mouse embryos. When these animals matured, three of themcontained the transgenes. Tissues taken from their progeny "revealedintense cardiac expression," but only in the heart muscle.Overexpression of the b-AR protein by these extra gene copies rangedfrom 55 to 195 times the number of receptors occurring naturally incontrol tissues. And those over-expressed receptors exerted three timesthe muscular pressure on atrial tissue taken from transgenic mice as didthe normal molecule in controls.As the Science paper noted, recently developed techniques make itpossible to do cardiac catheterization on live, anesthetized mice. TheDuke group measured blood-flow dynamics by this in vivo probe atvarious points in the hearts of transgenic and control animals. A typicalreading: baseline left ventricle pressures were 70 percent greater in theformer. To bring the controls up to that level required escalatingadministration of a synthetic epinephrine which gained access to theircells via the excess receptor.Paradoxically, when the researchers cut off the epinephrine, the heartscontinued to beat just as strongly. Lefkowitz construes this paradox asmeaning that the great increase of b2-adrenergic receptors in thecardiac cells stimulated them without need for outside hormone.The left ventricle is the heart's key component in supporting blood-flow throughout the body. In the transgenic mice, the Science paperstated, this systemic circulation "has been converted to a maximalinotropic [muscle-contraction] state . . ."Receptor biologist Lefkowitz is now preparing to produce mousemodels with induced congestive heart failure, he told BioWorld, toconfirm his strategy's therapeutic effect. Before human gene therapycan be contemplated, he added, "we must learn how to get the receptorgene into adult hearts, instead of into single-cell embryos." He and hisassociates are beginning to recruit adenoviral vectors for such a genedelivery system.
-- David N. Leff Science Editor
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