Downregulation of cardiac inflammation via the CaMKII δ/NF-κB pathway in heart failure by Lonicerae Japonicae Flos and Angelicae Sinensis Radix

Background: Inflammation serves an essential function in the occurrence and progression of heart failure (HF), especially in the early stage. Lonicerae japonicae Flos (LJF), Angelicae sinensis Radix (ASR), and their compatibility (LJF+ASR) can inhibit excessive inflammation and have significant cardioprotective effects. However, the primary active ingredients and mechanism of LJF and ASR in anti-inflammatory and anti-HF effect remain to be elucidated.

Purpose: This study aimed to evaluate the influence of LJF, ASR, and LJF+ASR on early inflammation and subsequent cardiac function in HF mice and to identify the primary pharmacologically active components of these compounds.

Methods: LJF, ASR, and LJF+ASR components entering the plasma and heart were identified via UPLC-LTQ-Orbitlaps-MSⁿ. The cardioprotective effects of LJF, ASR, and LJF+ASR after 8 weeks of treatment were validated in transverse aortic constriction (TAC)-induced HF mice via echocardiography, HE staining, and cardiac indices. The anti-inflammatory effects of these treatments after 1 week of TAC induction, as well as the cardioprotective and anti-inflammatory effects of the primary component chlorogenic acid (CGA), were confirmed in H9c2 cardiomyocytes through flow cytometry, Western blot, and siRNA transfection.

Results: LJF, ASR and LJF+ASR enhanced cardiac contractile function and ameliorated cardiac pathological remodeling induced by TAC. Moreover, these compounds inhibited platelet-granulocyte aggregation, platelet-monocyte aggregation, the calmodulin-dependent protein kinase II delta (CaMKII δ)/nuclear factor-kappaB (NF-κB) signaling pathway and proinflammatory factor levels in early-stage HF to different extents. Moreover, 9 potentially effective components were identified in the aqueous extract and blood-absorbed components of LJF+ASR, and CGA inhibited the CaMKII δ/NF-κB signaling pathway and decreased proinflammatory factor levels in vitro.

Conclusion: LJF, ASR, LJF+ASR and CGA inhibit the CaMKII δ/NF-κB signaling pathway and are potentially novel therapeutics for mitigating early inflammation and improving late cardiac function of HF.