Targeting calcium signaling by inositol trisphosphate receptors: A novel mechanism for the anti-asthmatic effects of Houttuynia cordata.

Asthma is a chronic inflammatory disease characterized by airway hypersensitivity and remodeling. The current treatments provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because intracellular calcium (Ca) signaling plays an essential role in regulating the contractility and remodeling of airway smooth muscle cells, the targeting of Ca signaling is a potential therapeutic strategy for asthma. Houttuynia cordata is a traditional Chinese herb that is used to treat asthma due to its anti-allergic and anti-inflammatory properties. We hypothesized that H. cordata might modulate intracellular Ca signaling and could help relieve asthmatic airway remodeling. We found that the mRNA and protein levels of inositol trisphosphate receptors (IPRs) were elevated in interleukin-stimulated primary human bronchial smooth muscle cells and a house dust mite-sensitized model of asthma. The upregulation of IPR expression enhanced intracellular Ca release upon stimulation and contributed to airway remodeling in asthma. Intriguingly, pretreatment with H. cordata essential oil rectified the disruption of Ca signaling, mitigated asthma development, and prevented airway narrowing. Furthermore, our analysis suggested that houttuynin/2-undecanone could be the bioactive component in H. cordata essential oil because we found similar IPR suppression in response to the commercially available derivative sodium houttuyfonate. An in silico analysis showed that houttuynin, which downregulates IPR expression, binds to the IP binding domain of IPR and may mediate a direct inhibitory effect. In summary, our findings suggest that H. cordata is a potential alternative treatment choice that may reduce asthma severity by targeting the dysregulation of Ca signaling.