Danhong Injection targets CaMKII through Dihydrotanshinone I to alleviate cardiomyocyte death and inflammation in viral myocarditis

Viral myocarditis, an inflammatory heart disorder caused by viral infections, often leads to poor outcomes due to the lack of effective prevention and treatment strategies. Despite the characteristic feature of cardiomyocyte death in this condition, the underlying mechanisms and potential therapeutic approaches remain poorly understood. Traditional Chinese medicine (TCM), despite its extensive history in treating various diseases, has not yet been approved for the treatment of viral myocarditis. Here, we screened six TCM patent injections recommended by clinical practice guidelines for treating cardiovascular diseases and discovered that Danhong Injection (DHI) markedly reduced cardiomyocyte death induced by Coxsackievirus B3 (CVB3). Additionally, in a CVB3-infected mouse model of viral myocarditis, DHI treatment notably alleviated cardiomyocyte death (including apoptosis, necroptosis and pyroptosis), as well as inflammation, cardiac dysfunction, and mortality. Mechanistically, DHI exerted its protective effects by inhibiting CaMKII through its active monomer Dihydrotanshinone I (Dih-I), identified as a CaMKII inhibitor. In viral myocarditis patients, CaMKII phosphorylation was upregulated in the hearts. The anti-inflammatory properties and CaMKII inhibition effects of DHI were further validated in primary human peripheral blood mononuclear cells. Our findings not only demonstrate the central role of CaMKII-mediated cardiomyocyte death in the progression of viral myocarditis, but also highlight DHI as a promising therapeutic intervention for managing viral myocarditis-induced cardiac injury and related pathological response.