Dynamics of cardiomyocyte gene expression and reversibility of catecholamine-induced heart injury

Abstract

Abstract Introduction Catecholamines such as adrenaline and noradrenaline are key regulators of cardiac function in response to increased demand due to stress, illness, or injury, and are used as therapeutic drugs in intensive care medicine. Continuous overactivation of adrenergic receptors, e.g. in heart failure, clearly aggravates detrimental cardiac remodeling, however, whether transient adrenergic stimulation causes persistent myocardial injury remains debated. In this study, we asked whether the structural alterations of the heart induced by adrenergic stimulation are reversible and investigated the molecular mechanisms involved in the remodeling and reverse remodeling process. Methods and results Wild-type mice were assigned to 14 days treatment with isoprenaline and phenylephrine (IsoPE), treatment with IsoPE and subsequent recovery, or healthy control groups. IsoPE induced substantial cardiac fibrosis and hypertrophy without signs of functional impairment during echocardiography. RNA sequencing from cardiomyocyte nuclei isolated by flow cytometry revealed marked changes in gene expression after IsoPE treatment (295 differentially expressed genes) related to transforming growth factor signaling, vasculature development, or extracellular matrix organization. Analysis of enhancer regions that were linked to differentially expressed genes identified AP-1 family members Jun and Fos as key drivers of these processes and predicted their direct target genes in cardiomyocytes. IsoPE induced marked changes in the gene expression of adrenergic receptors and their downstream signaling pathways in cardiomyocytes that may be related to receptor desensitization. Within two weeks after IsoPE withdrawal, structural remodeling of the heart recovered and ~95 % of genes that were differentially expressed with IsoPE treatment returned to baseline expression. Conclusion We demonstrate here that prolonged catecholamine treatment at doses that induce left ventricular hypercontractility, but no overt heart failure, resulted in significant yet reversible cardiac injury. Immediate early transcription factors such as Jun and Fos were identified as main drivers of IsoPE induced pathological gene expression in cardiomyocytes.