Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Li S

PROVIDER: S-EPMC5569633 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Li Sinai S Nong Yibing Y Nong Yibing Y Gao Qun Q Liu Jing J Li Yan Y Cui Xiaoyun X Wan Jie J Lu Jinjin J Sun Mingjie M Wu Qian Q Shi Xiaolu X Cui Haifeng H Liu Weihong W Zhou Mingxue M Li Lina L Lin Qian Q

Evidence-based complementary and alternative medicine : eCAM 20170810

<h4>Background</h4><i>Astragalus</i> was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from <i>Astragalus</i>, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca<sup>2+</sup> current (<i>I</i><sub>Ca-L</sub>) in HF mice by the downregulation of Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII).<h4>Met ...[more]

PMID: 28855948

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Project description:Background Arginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase ( eNOS ). We tested the hypotheses that arginase II activity participates in the regulation of Ca2+/Ca2+/calmodulin-dependent kinase II / eNOS activation, and this process is dependent on mitochondrial p32. Methods and Results Downregulation of arginase II increased the concentration of cytosolic Ca2+ ([Ca2+]c) and decreased mitochondrial Ca2+ ([Ca2+]m) in microscopic and fluorescence-activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca2+/Ca2+/calmodulin-dependent kinase II . These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca2+ from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II -null mice resulted in reduced p32 protein level. In the aortas of wild-type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO -dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca2+]m were increased in the aortas from apolipoprotein E (ApoE-/-) mice fed a high-cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca2+/Ca2+/calmodulin-dependent kinase II -dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice. Conclusions These data demonstrate a novel function of arginase II in regulation of Ca2+-dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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