Loss of α7 nicotinic acetylcholine receptor exacerbates adrenergic-induced cardiac damage

Previous studies have implicated the α7 nicotinic acetylcholine receptor (α7nAChR) in cardioprotection via its anti-inflammatory effects, yet the underlying mechanisms remain poorly understood. Here, we investigated the impact of α7nAChR deficiency on cardiac injury induced by a 7-day isoproterenol (ISO) treatment in littermate wild-type (WT) and α7nAChR-knockout (α7-KO) mice. ISO administration in WT mice led to a marked upregulation of α7nAChR expression in cardiac tissue and isolated cardiomyocytes, suggesting a compensatory response to adrenergic stress. To investigate this hypothesis, we assessed ISO-induced structural and inflammatory changes in both genotypes. ISO-treated WT mice developed isolated cardiac hypertrophy with minimal inflammation or fibrosis. In contrast, α7-KO mice subjected to ISO treatment displayed exacerbated hypertrophy and fibrosis. These alterations were accompanied by marked leukocyte accumulation, supporting the anti-inflammatory role of α7nAChR. To explore this further, we characterized the inflammatory profile using flow cytometry. FACS-analyzed hearts from α7- KO/ISO mice exhibited increased monocyte infiltration and a marked expansion of the CCR2 + population compared to WT/ISO. This phenotype was associated with greater cardiomyocyte death. In vitro, isolated ventricular myocytes lacking α7nAChR were intrinsically more susceptible to ISO-induced cytotoxicity, indicating that α7nAChR exerts a cell-autonomous protective role beyond its anti-inflammatory function. Our findings establish α7nAChR as a key determinant of cardiac resilience to adrenergic insult and underscore its potential as a therapeutic target for mitigating myocardial injury.