Immune cell β2-adrenergic receptors contribute to the development of heart failure

beta-Adrenergic receptors (beta ARs) regulate normal and pathophysiological heart function through their impact on contractility. beta ARs 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 beta(2)AR 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 PAR activation and contributing to the detrimental effects in the heart. We hypothesized that immune cell beta(2)AR 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 beta(2)AR knockout (KO) donors. WT and beta(2)ARKO BMT mice were chronically administered the beta AR 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 beta(2)ARKO BMT animal. beta(2)ARKO 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 beta(2)AR expression in the heart's response to chronically elevated catecholamines. NEW & NOTEWORTHY Immune cell beta(2)-adrenergic receptors (beta(2)ARs) are important for proinflammatory macrophage infiltration to the heart in a chronic isoproterenol administration model of heart failure. Mice lacking immune cell beta(2)AR 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 beta(2)AR regulation of immune responses plays an important role in the heart's response to persistent beta AR stimulation.

Automated summary

This study demonstrates the important role of immune cell beta(2)AR in regulating inflammation and cardiac function in response to chronic catecholamine elevations. Mice lacking immune cell beta(2)AR showed decreased immune cell infiltration and improved cardiac outcomes when exposed to beta AR agonist isoproterenol. The findings suggest that beta(2)AR regulation of immune responses is crucial for the heart's response to prolonged beta adrenergic stimulation.