Astragalus Granule Prevents Ca²⁺ Current Remodeling in Heart Failure by the Downregulation of CaMKII

Astragalus was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from Astragalus, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca²⁺ current (I_Ca-L) in HF mice by the downregulation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII).

HF mice were induced by thoracic aortic constriction (TAC). After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP) and I_Ca-L. The expressions of L-type calcium channel alpha 1C subunit (Cav1.2), CaMKII, and phosphorylated protein kinase A (p-PKA) were examined by western blot.

The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered I_Ca-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG-related shortened repolarization time, decreased peak I_Ca-L, accelerated I_Ca-L inactivation, and positive frequency-dependent I_Ca-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart.

AG treatment protected the failing heart against electrical remodeling and I_Ca-L remodeling by downregulating CaMKII.