β₂-Adrenergic receptor disruption exacerbates cardiac injury and fibroblast activation in a female mouse model of...

Takotsubo cardiomyopathy (TTC) is an acute stress-induced cardiac syndrome that predominantly affects women and is driven by surges in catecholamines that excessively activate β-adrenergic receptors (βARs). Although β₁AR signaling mediates much of the injury, β₂ARs have recognized cytoprotective roles in other cardiac settings, yet their contribution to TTC-associated remodeling remains unclear. To address this gap, we induced a TTC-like phenotype in female wild-type (WT) and β₂AR-deficient (β₂AR^-/-) mice with a single high dose of isoproterenol (ISO). After ISO injection, β₂AR^-/- mice exhibited exacerbated myocardial injury, characterized by greater hypertrophy and higher levels of apoptosis and necrosis compared with WT/ISO mice. This heightened injury was accompanied by a more robust inflammatory response, including increased inflammatory score, enhanced CD68⁺ macrophage infiltration, and marked recruitment of CCR2⁺MHC-II^low monocytes. β₂AR^-/-/ISO hearts also displayed more extensive interstitial fibrosis. Because fibrosis is a key driver of long-term functional decline, we isolated cardiac fibroblasts (CFs) and characterized their activation state. CFs from β₂AR^-/-/ISO hearts displayed a significantly higher percentage of α-SMA⁺ cells, increased Collagen 3 and MMP-2 staining, along with upregulation of profibrotic genes (Col1a1, Col3a1, Fap). Functionally, β₂AR^-/-/ISO CFs exhibited an activated molecular signature enriched in cytokines and growth factors, and their conditioned media induced greater hypertrophy in neonatal cardiomyocytes, revealing a potent paracrine contribution to the remodeling process. These findings demonstrate that the female heart relies on β₂AR signaling to limit acute catecholamine-induced injury, underscoring the potential of β₂AR-targeted interventions as therapeutic strategies in a Takotsubo-like setting.NEW & NOTEWORTHY Takotsubo cardiomyopathy (TTC) disproportionately affects women and is driven by excessive β-adrenergic receptor (βAR) activation. We show that loss of β₂AR signaling exacerbates myocardial injury, creating a proinflammatory and profibrotic milieu that amplifies fibroblast activation and reshapes their paracrine profile. These activated cardiac fibroblasts (CFs) further sustain cardiomyocyte hypertrophy, perpetuating the injury loop in β₂AR-deficient hearts. These findings establish β₂AR as a determinant of cardiac resilience and support β₂AR-directed strategies as interventions in the acute phase of TTC.