Astragalus Granule Prevents Ca 2+ Current Remodeling in Heart Failure by the Downregulation of CaMKII.

BACKGROUND: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSION: AG treatment protected the failing heart against electrical remodeling and I Ca-L remodeling by downregulating CaMKII.