SUMOylation of SIRT1 activating PGC-1α/PPARα pathway mediates the protective effect of LncRNA-MHRT in cardiac hypertrophy

Abstract

Long noncoding RNA-Myosin heavy chain associated RNA transcript (LncRNA-MHRT) has been reported to prevent pathological cardiac hypertrophy. However, the underlying inhibition mechanism has not been fully elucidated. Further, whether MHRT inhibits hypertrophy by regulating post-translational modification of certain proteins remains unclear. Therefore, this study aims to find potential role of MHRT in inhibiting cardiac hypertrophy via regulating modification of certain proteins. Here, Angiotensin II (Ang II) -treated neonatal rat cardiomyocytes and transverse aortic constriction (TAC) mice were used to investigate the effect and mechanism of MHRT in cardiac hypertrophy in vitro and in vivo. Moreover, the regulatory effects of MHRT on SUMOylation of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α)/peroxisome proliferator-activated receptor-α (PPARα), specificity protein 1 (SP1)/histone deacetylase 4 (HDAC4) pathway were investigated. Here, we found that MHRT improved heart function by attenuating pathological cardiac hypertrophy in vivo and in vitro. MHRT also promoted the SUMOylation of SIRT1 protein that activated PGC1-α/PPAR-α pathway. Furthermore, MHRT enhanced SUMOylation of SIRT1 by upregulating SP1/HDAC4. Our findings suggested that SUMOylation of SIRT1 could mediate the protective effect of MHRT in cardiac hypertrophy. The new regulatory pathway provides a potential new therapeutic target for pathological cardiac hypertrophy.

Keywords: Cardiac hypertrophy; LncRNA-MHRT; SIRT1; SUMO1.