Immune cell ß2-adrenergic receptors contribute to the development of heart failure.

ABSTRACT

ß-Adrenergic receptors (ßARs) regulate normal and pathophysiological heart function through their impact on contractility. ßARs are also regulators of immune function where they play a unique role depending on the disease condition and immune cell type. Emerging evidence suggests an important role for the ß2AR subtype in regulating remodeling in the pathological heart; however, the importance of these responses has never been examined. In heart failure, catecholamines are elevated, leading to chronic ßAR activation and contributing to the detrimental effects in the heart. We hypothesized that immune cell ß2AR plays a critical role in the development of heart failure in response to chronic catecholamine elevations through their regulation of immune cell infiltration. To test this, chimeric mice were generated by performing bone marrow transplant (BMT) experiments using wild-type (WT) or ß2AR knockout (KO) donors. WT and ß2ARKO BMT mice were chronically administered the ßAR agonist isoproterenol. Immune cell recruitment to the heart was examined by histology and flow cytometry. Numerous changes in immune cell recruitment were observed with isoproterenol administration in WT BMT mice including proinflammatory myeloid populations and lymphocytes with macrophages made up the majority of immune cells in the heart and which were absent in ß2ARKO BMT animal. ß2ARKO BMT mice had decreased cardiomyocyte death, hypertrophy, and interstitial fibrosis following isoproterenol treatment, culminating in improved function. These findings demonstrate an important role for immune cell ß2AR expression in the heart's response to chronically elevated catecholamines.NEW & NOTEWORTHY Immune cell ß2-adrenergic receptors (ß2ARs) are important for proinflammatory macrophage infiltration to the heart in a chronic isoproterenol administration model of heart failure. Mice lacking immune cell ß2AR have decreased immune cell infiltration to their heart, primarily proinflammatory macrophage populations. This decrease culminated to decreased cardiac injury with lessened cardiomyocyte death, decreased interstitial fibrosis and hypertrophy, and improved function demonstrating that ß2AR regulation of immune responses plays an important role in the heart's response to persistent ßAR stimulation.