| First Author | Cao HJ | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 137 |
| Pages | 34-45 | PubMed ID | 31629736 |
| Mgi Jnum | J:292853 | Mgi Id | MGI:6451230 |
| Doi | 10.1016/j.yjmcc.2019.09.010 | Citation | Cao HJ, et al. (2019) Genetic ablation and pharmacological inhibition of immunosubunit beta5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice. J Mol Cell Cardiol 137:34-45 |
| abstractText | Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit beta5i (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/6J wild-type (WT) and beta5i knockout (beta5i 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 21days of DOCA-salt treatment, beta5i 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 beta5i KO mice. These findings were verified in beta5i 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 beta5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of beta5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-beta1/Smad2/3, NOX, and NF-kappaB), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of beta5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of beta5i may be a promising therapeutic target for the treatment of hypertensive heart diseases. |
