Beta-adrenergic receptors (beta-ARs) ptay a fundamental role in the regulation of cardiovascular function. The stimulation of cardiac beta-ARs effects increases in both the rate and force of cardiac comraction, and has additional effects on cardiac cell growth and apoptosis, beta-ARs represent one of the primary mechanisms by which sympathetically derived catecholamines modulate cardiovascular function. Heart failure, characterized by the inability of the heart to pump enough blood to meet the metabolic demands of the body, is associated with attenuated beta-AR signaling. The decrease in beta-AR function is directly related to an increase in the desensitization and down-regulation of beta-ARs, involving receptor phosphorylation by G protein-coupled receptor kinases (GRKs) and the subsequent binding of beta-arrestin. Numerous studies have demonstrated decreased nitric oxide (NO) bioavailability associated with heart failure. The transgenic overexpression of endothelial nitric oxide synthase (eNOS), a constitutively expressed isoform of the enzyme that produces NO, has been shown to attenuate experimental heart failure. Conversly, the inhibition of NOS leads to the development of tachyphylaxis to the vasodilator effects of beta-AR agonists, which can be rescued by the addition of NO containing S-nitrosothiols (SNOs). This suggests that compromised NO bioavailability leads to a decrease in the ability of beta-ARs to signal, similar to that which is observed in heart failure. These findings provide converging lines of evidence that NO bioavailability is fundamental for the homeostatic regulation of beta-AR function. Preliminary data from our lab suggests that nitrosothiols prevent the activated beta2-AR from associating with the cellular machinery involved in desensitization and down-regulation. Specifically, we demonstrate that the nitrosothiols, L-SNC & GSNO, inhibit GRK2-mediated phosphorylation of the beta2-AR and prevent its subsequent interaction with beta-arrestin2. We further demonstrate that increasing levels of the endogenous nitrosothiol, GSNO, prevents beta-AR down-regulation and delays the onset of experimental heart failure. Our Central Hypothesis is that NO bioavaitability regulates beta-AR function, preventing the desensitization and down-regulation of beta-ARs. Altered beta-AR receptor function associated with heart failure is the direct result of decreased NO bioavailability.
The Specific Aims are (1) To test whether NO bioavailability directly modulates beta-AR signaling by assessing agonist induced beta-AR desensitization and down-regulation in cultured cells; (2) To determine whether NO/nitrosothiols alter beta-AR stimulated G protein coupling, and GRK-& PKA-mediated receptor phosphorylation using purified proteins in a reconstituted system; (3) To test whether endogenous nitrosothiols modulate cardiac beta-AR function and the progression of experimental heart failure (HF) in the mouse; (4) To test nitrosothiol-based therapies as a novel therapeutic modality for improving cardiac function in both small (mouse) and large (rabbit & pig) animal models of cardiac hypertrophy and/or heart failure.
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