The most common cause of chronic heart failure in the U.S. is a primary or secondary dilated cardiomyopathy (DCM). Recent data have demonstrated unequivocally that dysregulation of the adrenergic nervous system is a major determinant in the natural history of DCM and clinical heart failure. Excessive, sustained cardiac adrenergic drive contributes to both contractile dysfunction and pathological hypertrophy/remodeling. Most of these adverse effects are delivered through the beta1-adrenergic receptor subtype, which in the failing human heart is dominant by virtue of its proportion (60-70% of the total beta-receptor population), high affinity for norepinephrine, and coupling to adverse biologic effects that include the induction of fetal genes and pathological hypertrophy, apoptosis, and multiple desensitization phenomena. This proposal investigates two timely and highly important issues in norepinephrine-beta1-adrenergic signaling in the failing human heart: 1) the effects of adrenergic receptors polymorphism that regulate norepinephrine release and beta1-receptor function, and 2) the molecular mechanism(s) by which increased beta1-adrenergic signaling leads to myocardial fetal gene induction. With regard to adrenergic receptor polymorphisms, a loss of function polymorphism (alpha2CDEL322-325) in the presynaptically positioned alpha2C-receptor, which when occupied by agonist inhibits norepinephrine release, will be investigated for its hypothesized ability to increase cardiac norepinephrine release. A gain of function beta1-receptor polymorphism (beta1Arg389) will be investigated for its potential ability to deliver an increased beta-agonist mediated contractile response in the nonfailing human heart, but a diminished response in the failing heart. For the molecular basis of beta1-adrenergic mediation of fetal gene induction, an hypothesis involving activation of fetal gene transcription by derepression of myocyte enhancer factor 2 (MEF2) related to nuclear export of Class II histone deacetylases will be tested. For the 2nd component of fetal gene induction, down-regulation in adult genes, a hypothesis involving the up-regulation of the repressor transcription factors YY1 and ERF will be tested. Experimental systems include intact and isolated nonfailing and failing human hearts, transgenic mice with cardiac restricted overexpression of the human beta1-adrenergic receptor, and human alpha-myosin heavy chain promoter-reporter constructs.

R01HL048013

1993-05-01

2009-02-28