Yiqi Huoxue formula improved heart failure with reduced ejection fraction in transgenic mice by inhibiting CaMKIIδB and CaMKIIδC overexpression and increasing SERCA2a expression.
Does Yiqi Huoxue formula improve cardiac function and calcium homeostasis in transgenic mouse models of HFrEF?
Yiqi Huoxue formula improves heart failure with reduced ejection fraction in transgenic mice by inhibiting myocardial remodeling and enhancing calcium homeostasis.
OBJECTIVE: To confirm the efficacy of Yiqi Huoxue formula (益气活血方, YQHX) on heart failure with reduced ejection fraction (HFrEF), and elucidate its potential effect on calcium homeostasis. METHODS: Cardiac specific calcium/calmodulin-dependent protein kinase II delta C isoform (CaMKⅡδC)-overexpression transgenic mice (C-CaMKⅡδC(+/-) Tg mice) and calcium/calmodulin-dependent protein kinase II delta B isoform (CaMKⅡδB)-overexpression transgenic mice (C-CaMKⅡδB(+/-) Tg mice) were established by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technique, and their genotypes and phenotypes were identified thereafter. C57BL/6 mice and transgenic mice were divided into seven groups in random, each containing eight mice. The groups were Control group, CaMKⅡδB model group, CaMKⅡδB treatment group (B Treated), CaMKⅡδB inhibitor group (B Inhibitor), CaMKⅡδC model group (C Model), CaMKⅡδC treatment group (C Treated), CaMKⅡδC inhibitor group (C Inhibitor). B and C Treated groups were given YQHX once a day for 4 weeks by gavage. The cardiac function and structure were evaluated using echocardiogram. The myocardial cellular status and fibrosis were detected by hematoxylin and eosin staining and Masson staining. Calcium transients and calcium leakage from cardiac ventricular myocytes were detected to reflect calcium homeostasis, and the expressions of CaMKⅡδB, CaMKⅡδC, hypertrophy factors, calcium pathway-related genes, and the level of calcium handling proteins were assessed by western blotting and reverse transcription-quantitative polymerase chain reaction. RESULTS: We found CaMKⅡδB and CaMKⅡδC transgenic mice showed HFrEF phenotype. YQHX improved the systolic function of the CaMKⅡδB transgenic mice, reduced the cross-sectional area of cardiomyocytes, inhibited the overexpression of CaMKⅡδB and hypertrophy-related genes (B-type natriuretic peptide, myocyte enhancer factor 2, and atrial natriuretic factor), and increased calcium handling protein sarcoendoplasmic reticulum Ca(2+) adenosine triphosphatase 2a (SERCA2a) and calcium capacity. YQHX improved the cardiac systolic function of CaMKⅡδC transgenic mice, reduced the ventricular diameter and cardiomyocyte cross-sectional area, alleviated myocardial fibrosis, increased SERCA2a expression and calcium capacity, and reduced calcium leakage. CONCLUSION: Our results suggest that YQHX improved HFrEF by inhibiting CaMKIIδB overexpression, which may be related to reduced expression of hypertrophy-related factors, and increased SERCA2a expression to increase calcium reserve. In addition, YQHX improved HFrEF by inhibiting CaMKIIδC overexpression, which may be related to reduce calcium leakage, and increase SERCA2a expression to increase calcium reserve.
Xu et al. (Sat,) conducted a other in Heart failure with reduced ejection fraction (HFrEF) (n=56). Yiqi Huoxue formula (YQHX) vs. Model group was evaluated on Cardiac systolic function, myocardial remodeling, and calcium homeostasis. Yiqi Huoxue formula improved heart failure with reduced ejection fraction in transgenic mice by inhibiting CaMKIIδB and CaMKIIδC overexpression and increasing SERCA2a expression.