Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of β-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies.

Adrenergic pathways represent the main channel of communication between the nervous system and the immune system. During inflammation, blood monocytes migrate within tissue and differentiate into macrophages, which polarize to M1 or M2 macrophages with tissue-damaging or -reparative properties, respectively. This study investigates whether the β-adrenergic receptor (β-AR)-blocking drug propranolol modulates the monocyte-to-macrophage differentiation process and further influences macrophages in their polarization toward M1- and M2-like phenotypes. Six-day-human monocytes were cultured with M-CSF in the presence or absence of propranolol and then activated toward an M1 pro-inflammatory state or an M2 anti-inflammatory state. The chronic exposure of monocytes to propranolol during their differentiation into macrophages promoted the increase in the M1 marker CD16 and in the M2 markers CD206 and CD163 and peroxisome proliferator-activated receptor ɣ expression. It also increased endocytosis and the release of IL-10, whereas it reduced physiological reactive oxygen species. Exposure to the pro-inflammatory conditions of propranolol-differentiated macrophages resulted in an anti-inflammatory promoting effect. At the molecular level, propranolol upregulated the expression of the oxidative stress regulators NRF2, heme oxygenase-1 and NQO1. By contributing to regulating macrophage activities, propranolol may represent a novel anti-inflammatory and immunomodulating compound with relevant therapeutic potential in several inflammatory diseases.

Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether β-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of β-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a β-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a β2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the β2-AR stimulation. We conclude that the crosstalk between the β2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy.

Altered β-adrenergic receptor (β-AR) density has been reported in cells, animals, and humans receiving β-blocker treatment. In some cases, β-AR density is upregulated, but in others, it is unaffected or even reduced. Collectively, these results would imply that changes in β-AR density and β-blockade are not related. However, it has still not been clarified whether the effects of β-blockers on receptor density are related to their ability to activate different β-AR signaling pathways. To this aim, five clinically relevant β-blockers endowed with inverse, partial or biased agonism at the β₂-AR were evaluated for their effects on β₂-AR density in both human embryonic kidney 293 (HEK293) cells expressing exogenous FLAG-tagged human β₂-ARs and human lymphocytes expressing endogenous β₂-ARs. Cell surface β₂-AR density was measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Treatment with propranolol, carvedilol, pindolol, sotalol, or timolol did not induce any significant change in surface β₂-AR density in both HEK293 cells and human lymphocytes. On the contrary, treatment with the β-AR agonist isoproterenol reduced the number of cell surface β₂-ARs in the tested cell types without affecting β₂-AR-mRNA levels. Isoproterenol-induced effects on receptor density were completely antagonized by β-blocker treatment. In conclusion, the agonistic activity of β-blockers does not exert an important effect on short-term regulation of β₂-AR density.

Background: This study is part of the HEAL ITALIA partnership, funded by the National Recovery and Resilience Plan (PNRR) and the European Union. Heart failure (HF) is a serious health problem, with a reduced density of the β1-adrenergic receptor (β1-AR) in the myocardium as a hallmark. It is unclear whether this downregulation causes dysfunction or represents an epiphenomenon. Recent evidence implicates oxidative stress and mitochondrial signaling, particularly through the 18 kDa translocator protein (TSPO), in the regulation of the β1-AR, with possible modulation by estrogen. Objectives: To determine (1) the role of β1-AR desensitization in the onset and development of HF; (2) whether monocytes can represent a suitable ex vivo model for sex-oriented mechanistic studies in the cardiac field; (3) whether monocytes isolated from peripheral blood of patients can represent a diagnostic and/or therapy response biomarker by monitoring β1-AR density; (4) whether and how the mitochondrial receptor TSPO is involved in the β1-AR dysregulation observed in HF; and (5) whether the mechanisms linked to the onset of HF are regulated in a sex-specific manner through the effect of estrogen and/or the X chromosome on the expression of specific microRNAs. Methods: Using an integrated in vitro-ex vivo-in vivo methodological approach, we will evaluate the density of β1/β2-AR receptors, the downstream signaling (GRK2/β-arrestin), mitochondrial and redox parameters, and miRNA profiles in human monocytes and cardiomyocytes, and in mouse hearts after HF following pressure overload. Conclusions: The goal is to better understand the mechanisms underlying β1-AR desensitization, verify monocytes as peripheral markers of disease progression and response to therapy, and provide potentially useful information for the development of gender-specific therapies for heart failure.