Dataset Information

The proteasome activator REG? accelerates cardiac hypertrophy by declining PP2Ac?-SOD2 pathway.

ABSTRACT: Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REG? is emerging as 11S proteasome activator of 20S proteasome to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner. Here, we found that REG? was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REG? deficiency ameliorated pressure overload-induced cardiac hypertrophy were associated with inhibition of cardiac reactive oxygen species (ROS) accumulation and suppression of protein phosphatase 2A catalytic subunit ? (PP2Ac?) decay. Mechanistically, REG? interacted with and targeted PP2Ac? for degradation directly, thereby leading to increase of phosphorylation levels and nuclear export of Forkhead box protein O (FoxO) 3a and subsequent of SOD2 decline, ROS accumulation, and cardiac hypertrophy. Introducing exogenous PP2Ac? or SOD2 to human cardiomyocytes significantly rescued the REG?-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REG? caused in vivo, thereby establishing a REG?-PP2Ac?-FoxO3a-SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REG?-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.

SUBMITTER: Xie Y

PROVIDER: S-EPMC7494903 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway.

Xie Yifan Y Gao Yang Y Gao Rifeng R Yang Wenlong W Dong Zheng Z Moses Robb E RE Sun Aijun A Li Xiaotao X Ge Junbo J

Cell death and differentiation 20200518 10

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REGγ is emerging as 11S proteasome activator of 20S proteasome to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner. Here, we found that REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REGγ deficiency ameliorated pressure overload-induced cardiac hypertrop ...[more]

PMID: 32424140

Similar Datasets

Project description:RationaleEndoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating transcription factor 6α), an inducer of genes that enhance protein folding and restore ER proteostasis. Because of increased protein synthesis, it is possible that protein folding and ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes.ObjectiveTo examine the activity and function of ATF6 during cardiac hypertrophy.Methods and resultsWe found that ER stress and ATF6 were activated and ATF6 target genes were induced in mice subjected to an acute model of transverse aortic constriction, or to free-wheel exercise, both of which promote adaptive cardiac myocyte hypertrophy with preserved cardiac function. Cardiac myocyte-specific deletion of Atf6 (ATF6 cKO [conditional knockout]) blunted transverse aortic constriction and exercise-induced cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for ATF6 in compensatory myocyte growth. Transcript profiling and chromatin immunoprecipitation identified RHEB (Ras homologue enriched in brain) as an ATF6 target gene in the heart. RHEB is an activator of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a major inducer of protein synthesis and subsequent cell growth. Both transverse aortic constriction and exercise upregulated RHEB, activated mTORC1, and induced cardiac hypertrophy in wild type mouse hearts but not in ATF6 cKO hearts. Mechanistically, knockdown of ATF6 in neonatal rat ventricular myocytes blocked phenylephrine- and IGF1 (insulin-like growth factor 1)-mediated RHEB induction, mTORC1 activation, and myocyte growth, all of which were restored by ectopic RHEB expression. Moreover, adeno-associated virus 9- RHEB restored cardiac growth to ATF6 cKO mice subjected to transverse aortic constriction. Finally, ATF6 induced RHEB in response to growth factors, but not in response to other activators of ATF6 that do not induce growth, indicating that ATF6 target gene induction is stress specific.ConclusionsCompensatory cardiac hypertrophy activates ER stress and ATF6, which induces RHEB and activates mTORC1. Thus, ATF6 is a previously unrecognized link between growth stimuli and mTORC1-mediated cardiac growth.

Dataset Information

The proteasome activator REG? accelerates cardiac hypertrophy by declining PP2Ac?-SOD2 pathway.

Publications

The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets