LncRNA GAS5 restrains ISO-induced cardiac fibrosis by targeting miR-217 through regulating SIRT1

Abstract

Abstract Aims: Considering the SIRT1 has the effect of improving myocardial fibrosis and GAS5 can inhibit the occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating miR-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Methods and Results: Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress long-chain non-coding RNA GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-β1 was used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with miR-217 mimics and miR-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1βand SIRT1 were conducted. The Results showed that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1β and SIRT1 in ISO treated mice and TGF-β1 treated MCFs. However, this effect was significantly weakened after miR-217 overexpression, but was further enhanced after knockdown of miR-217. Conclusion: miR-217 down-regulats the expression of SIRT1, then aggravates NLRP3 inflammasome activation-mediated pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced by NLRP3 inflammasome activation-mediated pyroptosis via regulating miR-217/SIRT1 pathway. This study provides significant experimental evidence suggesting LncRNA GAS5 to be a potential therapeutic target for cardiac fibrosis and other fibrotic diseases.