Abstract 52: Temporal Regulation Of Cardiac Cytokine Expression in Response to Chronic β-Adrenergic Receptor Stimulation

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Chronic catecholamine stimulation of β-adrenergic receptors (βAR) is ultimately deleterious during heart failure (HF). While alterations in cytokines contribute to HF pathogenesis and βAR have been demonstrated to regulate cytokines in different models of HF, a comprehensive understanding of this relationship is lacking. Thus, we sought to characterize the impact of chronic βAR signaling on cardiac cytokine expression in vivo. C57BL/6 mice underwent infusion with vehicle or isoproterenol (Iso; 3 mg/kg/day) via minipumps for 1 or 2 weeks and cardiac function was monitored via echocardiography. At study termination, hearts were excised and assessed for changes in hypertrophy, fibrosis and apoptosis, each of which were enhanced by Iso. Expression of cardiac transcripts were assessed via whole transcriptome analysis, where 780 and 689 transcripts were significantly altered at 1 and 2 weeks of Iso, respectively, with only 115 transcripts regulated similarly between the two cohorts. Significant changes in cytokine transcript expression was observed in response to chronic Iso and Ingenuity Pathway Analysis (IPA) predicted the involvement of additional upstream cytokine regulators potentially regulated by Iso. Transcriptome results and IPA predictions were confirmed via qRT-PCR. A cytokine array also confirmed temporally-distinct alterations in the expression of 42 cytokines at the protein level. Differential alterations in cytokine expression resulting from 1 versus 2 weeks of Iso infusion suggest that cytokine-directed therapies may have distinct temporally-dependent consequences on cardiac function and survival under conditions of chronic catecholamine stress.

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