Total Flavonoids of Astragalus Plays a Cardioprotective Role in Viral Myocarditis.

BACKGROUND: Viral myocarditis is initiated by viral infection of myocardial tissue leading to dilated cardiomyopathy and congestive heart failure. Recent studies have linked viral myocarditis with dysfunctions in endoplasmic reticulum (ER) mediated Ca(2+) homeostasis and the unfolded protein response (UPR). Currently there are no effective treatments for this viral infection. METHODS: We employed the use of a well-characterized pathogen coxsackievirus B3 (CVB3) to induce mouse viral myocarditis. After intraperitoneal administration of total flavonoids of Astragalus (TFA), we examined the protective effect of TFA on CVB3-induced heart function impairment and decreased calumenin mRNA levels. Furthermore, calumenin protein level was studied in vivo and in vitro with CVB3 infection in the presence or absence of TFA. The interaction between calumenin and the sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) was also tested in HL-1 cells. RESULTS: Whereas customarily we would expect that CVB3 infection would decrease mRNA and protein levels of the Ca(2+) binding ER chaperone calumenin, here TFA treatment prevented this decline in both CVB3 infected mice and in an in vitro system of infected HL-1 cardiomyocytes. CVB3 infection in HL-1 cells prevented the association of calumenin with the calcium mobilizing protein SERCA2, and TFA treatment rescued this interaction. CONCLUSIONS: This study identified that CVB3 infection promotes cardiomyocyte dysfunction by effecting expression levels and activity of the cardio protective ER chaperone calumenin. For the first time, TFA was shown to prevent loss of mRNA and protein levels of calumenin and also rescued the association of this protein with SERCA2.