Abstract 12710: Adipocyte-Derived Exosomal Lncrna Sbf2-as1 Promotes Diabetic Myocardial Fibrosis Through Regulating Hnrnpa1/nrf2 Pathway via Sumoylation

Abstract

Introduction: The inhibition of Nrf2 pathway is regarded as the dominant process that correlates with the pathogenesis of diabetic cardiomyopathy (DCM). Recently, accumulating evidence reveals that lncRNAs play key roles in regulating Nrf2 pathway. However, the underlying mechanisms remain unclear. Here, we found that adipocyte lncRNA SBF2-AS1 (SBF2-AS1) enhanced the SUMOylation of hnRNPA1, which subsequently facilitated the package of SBF2-AS1 into exosomes under high glucose conditions. Hypothesis: We hypothesized that AdEXO-SBF2-AS1 promotes diabetic myocardial fibrosis through regulating the hnRNPA1/Nrf2 pathway via SUMOylation. Methods: We examined the effect of exosomes from diabetic (db/db) mice-derived adipocytes on ANG-II-induced cardiac fibrosis and function in non-diabetic mice. In the invitro study, HG (33mmol/L)-induced AdEXO were cultured with adult human cardiac fibroblasts (aHCFs). Differentially expressed lncRNAs in AdEXO were screened using lncRNA sequencing. Results: Intramyocardial injection of diabetic AdEXO in the non-diabetic heart exacerbated myocardial fibrosis. Whereas administration of an exosomes biogenesis inhibitor attenuated cardiac fibrosis in diabetic mice. We identified SBF2-AS1 is a common molecule significantly increased in diabetic AdEXO and HG-stimulated non-diabetic AdEXO. After four weeks of ANG II infusion, EXO-db/dbWT-injected mice displayed significant fibrosis in the heart. However, interestingly, mice receiving SBF2-AS1-deficient db/db-EXO showed a decrease in cardiac fibrosis. Similarly, AdEXO-SBF2-AS1 promoted aHCFs proliferation and transformation capabilities in vitro. Mechanistically, SBF2-AS1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1, which facilitated its packaging into exosomes. Subsequently, exosomal SBF2-AS1 was specifically transmitted into aHCFs and epigenetically downregulated Nrf2 expression by decreasing H3K9 acetylation level in the Nrf2 promoter. Conclusions: Our findings highlight a novel mechanism whereby the AdEXO-mediated SBF2-AS1/hnRNPA1/Nrf2 regulatory axis promotes diabetic myocardial fibrosis in a SUMOylation-dependent manner and implicate SBF2-AS1 as an attractive therapeutic target for DCM.