Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice

J Mol Cell Cardiol. 2019 Dec:137:34-45. doi: 10.1016/j.yjmcc.2019.09.010. Epub 2019 Oct 17.

Abstract

Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit β5i (also named LMP7) is involved in angiotensin II-induced atrial fibrillation; however, its role in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. C57BL/6 J wild-type (WT) and β5i knockout (β5i KO) mice were subjected to uninephrectomy (sham) and DOCA-salt treatment for three weeks. Cardiac function, fibrosis, and inflammation were evaluated by echocardiography and histological analysis. Protein and gene expression levels were analyzed by quantitative real-time PCR and immunoblotting. Our results showed that after 21 days of DOCA-salt treatment, β5i expression and chymotrypsin-like activity were the most significantly increased factors in the heart compared with the sham control. Moreover, DOCA-salt-induced elevation of blood pressure, adverse cardiac function, chamber and myocyte hypertrophy, interstitial fibrosis, oxidative stress, and inflammation were markedly attenuated in β5i KO mice. These findings were verified in β5i inhibitor PR-957-treated mice. Moreover, blocking of PTEN (the gene of phosphate and tensin homolog deleted on chromosome ten) markedly attenuated the inhibitory effect of β5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of β5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-β1/Smad2/3, NOX, and NF-κB), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of β5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of β5i may be a promising therapeutic target for the treatment of hypertensive heart diseases.

Keywords: Cardiac remodeling; DOCA-salt; Immunoproteasome catalytic subunit; PTEN; β5i.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / complications
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Chymotrypsin / metabolism
  • Desoxycorticosterone Acetate
  • Fibrosis
  • Hypertension / complications
  • Hypertension / metabolism*
  • Hypertension / physiopathology*
  • Inflammation / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress
  • PTEN Phosphohydrolase / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Subunits / metabolism*
  • Signal Transduction
  • Up-Regulation
  • Ventricular Remodeling*

Substances

  • Protein Subunits
  • Desoxycorticosterone Acetate
  • PTEN Phosphohydrolase
  • Chymotrypsin
  • LMP7 protein
  • Proteasome Endopeptidase Complex