Abstract 299: Simultaneous Cardiac And Adrenal Small Molecule GPCR-Gβ? Inhibition Halts The Progression Of Pressure Overload Heart Failure

Abstract

Heart failure (HF) is a progressive disease with rapidly increasing rates of morbidity and mortality. Elevated sympathetic nervous system activity, a salient feature of HF progression, leads to pathologic attenuation and desensitization of β-adrenergic receptors (β-ARs) due in part to Gβγ-mediated signaling. In the current study, we assessed the hypothesis that the small molecule Gβγ inhibitor “gallein” is salutary in treating pre-existing HF in a clinically relevant model (pressure-overload HF model of mouse transverse aortic constriction (TAC)) by simultaneously normalizing adrenergic receptor signaling in the heart and the adrenal gland. Four weeks post-TAC, mice received daily i.p. injections of vehicle or gallein for eight weeks (n=6-8 per group). Serial echocardiography was performed through out the study. At the end of the experiment, hemodynamic studies were performed, mice were sacrificed, blood, heart, and adrenal glands were harvested for further analysis. Gallein treatment improved survival and cardiac function and reduced cardiac hypertrophy, remodeling, and fetal genes expression in TAC mice. On the molecular level, gallein recovered membrane β-AR density and attenuated GRK2-PI3Kγ membrane recruitment, and Akt-GSK-3β signaling in TAC hearts. A salutary adrenal effect of gallein was obtained in cultured mice adrenal glands and human pheochromocytoma tissue (n=3), where direct gallein treatment restored α2-AR feedback inhibitory function and concurrently reduced catecholamine production. Moreover, gallein treatment attenuated adrenal hypertrophy in TAC mice and downregulated tyrosine hydroxylase and chromogranin A protein expression in adrenal glands from TAC mice and cultured pheochromocytoma tissue as well. In summary, our data suggest gallein as a systemic pharmacologic therapy with substantial therapeutic benefit in HF by simultaneously normalizing pathologic Gβγ-GRK2 signaling and recovering AR signaling in both the heart and the adrenal gland. In the heart, gallein mediated attenuation of cardiac remodeling probably involves inhibiting GRK2-PI3K-Akt signaling. Our data also suggest a role for small molecule Gβγ inhibition in other diseases of elevated catecholamine release, such as pheochromocytoma.