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Human single nuclear RNA sequencing identifies CD47 as a therapeutic target for doxorubicin-induced cardiomyopathy

ABSTRACT: Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, yet its underlying mechanisms remain incompletely understood. Identifying DoxCM mechanisms that can be translated into therapeutic interventions may improve patient outcomes. We performed single nuclear RNA-sequencing on left ventricular (LV) myocardial tissue from patients with DoxCM versus non-ischemic cardiomyopathy and non-failing donors. This approach aimed to elucidate the transcriptional changes associated with DoxCM. Additionally, we conducted immunostaining, flow cytometry, antibody neutralization, and cell depletion studies to validate our findings and define in vivo mechanisms.Compared to both donors and non-ischemic cardiomyopathy, LV myocardium from DoxCM patients exhibited increased periostin-positive (POSTN+) activated fibroblasts, down-regulation of genes involved in phagocytosis, and increased expression of the anti-phagocytic molecule CD47. Immunostaining of human cardiac sections and murine studies demonstrated increased POSTN+ cells and CD47 in DoxCM and in a murine breast cancer model. CD47 antibody neutralization both prevented and treated Dox-induced reduction in LV ejection fraction and fibrosis. Mechanistically, depletion of resident cardiac macrophages blocked the cardioprotective effects of CD47 neutralization and clearance of cardiac fibroblasts. Our data support CD47 as a disease-specific target and promising therapeutic approach for mitigating cardiac dysfunction in DoxCM

ORGANISM(S): Homo sapiens

PROVIDER: GSE292067 | GEO | 2025/08/18

REPOSITORIES: GEO

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Project description:Aims Ischemic cardiomyopathy with comorbid sleep apnea syndrome (SAS) is associated with worse long-term outcomes. Intermittent hypoxia (IH), a key feature of SAS, exacerbates sympathetic activity, hastening cardiac dysfunction and remodeling in ischemic cardiomyopathy rat models. This study explores whether targeted cardiac sympathetic denervation (CSD) can limit IH-induced progression of ischemic cardiomyopathy. Methods and results Male Wistar rats underwent myocardial infarction (MI) via permanent left coronary artery ligation, and CSD was simultaneously achieved through ablation of the left middle cervical and stellate ganglions. Rats were exposed to IH (21–5% fraction of inspired O2, 60 s cycle, 8 h/day) or normoxia (N) for 14 weeks starting 3 days post-surgery. Throughout the intervention period, cardiac sympathetic activity was assessed using spectral analysis of heart rate variability (HRV) from vigil ECG collected with a specialized jacket. Cardiac function and remodeling were monitored via echocardiography. Additionally, isolated cardiomyocytes from rats exposed to IH or N for 6 weeks were assessed for calcium transient, sarcomere shortening and adrenergic reserve using isoproterenol stimulation (100 nM). CSD reduced cardiac sympathetic activity and prevented IH-induced blunting of cardiomyocyte response to isoproterenol challenge. In hypoxic animals, CSD reduced alterations in long-term ejection fraction and mitigated cardiomyocyte hypertrophy. Transcriptomic analysis unveiled that CSD triggered biological processes related to cardiac repair and regeneration. Immunohistochemistry further supported these findings, demonstrating increased cardiomyocyte proliferation in the hypoxic group, as indicated by elevated Ki67 expression colocalized with MF20 markers. Conclusions Our data demonstrate that cardiac sympathetic denervation prevents IH-induced depletion of cardiac adrenergic reserve and deterioration of cardiac function in a rat model of ischemic cardiomyopathy. This study questions the role of sympathetic activity and hypoxia in cardiac regeneration and on the optimal management of sympathetic hyperactivity in ischemic cardiomyopathy in the specific context of associated SAS.

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Human single nuclear RNA sequencing identifies CD47 as a therapeutic target for doxorubicin-induced cardiomyopathy

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