Parasympathetic neuronal dysfunction is associated with heart failure (HF), yet the underlying mechanism is poorly understood. Here, we report that targeted vagal nerve stimulation (VNS) using optogenetics attenuated cardiac remodeling and HF induced by pressure overload. Unbiased approaches revealed that VNS decreased the proportion of Ccrl2+ macrophages, which were derived from myeloid monocytes and exhibited a distinct tumor necrosis factor alpha (TNF-α) cytokine-responsive, pro-hypertrophic, and profibrotic signature. Elimination of Ccrl2+ macrophages prevented cardiac remodeling and HF. Ccrl2+-macrophage-specific overexpression or global genetic loss of α7 nicotinic acetylcholine receptor (α7nAChR) highlighted their crucial contribution to VNS-mediated cardioprotection. Activation of α7nAChR inhibited Ccrl2+ macrophages' TNF-α responsiveness through increased expression of the transcription factor NRF2. Cardiac Ccrl2+ macrophages and TNF-α-responsive proteins positively correlated with cardiac remodeling and dysfunction in humans. An α7nAChR agonist effectively blocked the development of HF. These results suggest that the vagal neuroimmune axis modulates HF and is a promising target for treatment.

Beijing Anzhen Hospital of Capital Medical University Beijing China

Beijing Anzhen Hospital of Capital Medical University Beijing China; Beijing Institute of Heart Lung and Blood Vessel Diseases Beijing China

Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA

Innovation Center of Cardiometabolic Diseases Guangdong medical university Dongguan China; The Affiliated Dongguan Songshan Lake Central Hospital Dongguan China

Shenzhen Institute of Advanced Technology Shenzhen China

Citace poskytuje Crossref.org