Monoamine Oxidase-Dependent Pro-Survival Signaling in Diabetic Hearts Is Mediated by miRNAs

Abstract

Diabetes leads to cardiomyopathy and heart failure, the leading cause of death for diabetic patients. Monoamine oxidase (MAO) inhibition in diabetic cardiomyopathy prevents oxidative stress, mitochondrial and endoplasmic reticulum stress and the development of diastolic dysfunction. However, it is unclear whether, in addition to the direct effects exerted on the mitochondria, MAO activity is able to post-transcriptionally regulate cardiomyocyte function and survival in diabetes. To this aim, we performed gene and miRNA expression profiling in cardiac tissue from streptozotocin-treated mice (model of type 1 diabetes (T1D)), administered with either vehicle or MAOs inhibitor pargyline for 12 weeks. We found that inhibition of MAO activity in T1D hearts leads to profound transcriptomic changes, affecting autophagy and pro-survival pathways activation. MAO activity in T1D hearts increased miR-133a-3p, -193a-3p and -27a-3p expression. These miRNAs target insulin-like growth factor receptor 1 (Igf1r), growth factor receptor bound protein 10 and inositol polyphosphate 4 phosphatase type 1A, respectively, all components of the IGF1R/PI3K/AKT signaling pathway. Indeed, AKT activation was significantly downregulated in T1D hearts, whereas MAO inhibition restored the activation of this pro-survival pathway. The present study provides an important link between MAO activity, transcriptomic changes and activation of pro-survival signaling and autophagy in diabetic cardiomyopathy.

Monoamine oxidase A-dependent ROS formation modulates human cardiomyocyte differentiation through AKT and WNT activation

“…INPP4A is a lipid phosphatase that dephosphorylates PtdIns(3,4)P 2 to form PtdIns(4)P and PtdIns(3)P, acting as a negative regulator of the PI3K/AKT pathway. Recently, we showed that MAO activity is able to regulate miR-27a-3p levels that, in turn, binds Inpp4a mRNA and modulates its levels [ 10 ]. Taken together, these findings suggest that the activity of INPP4A is likely increased in MAO-A KO cells, thereby resulting in impaired signal transduction and AKT activation.…”

A landscape of mouse mitochondrial small non-coding RNAs

“…mmu-miR-122-5p chr 18 158456.4 Hand2, involved in mitochondrial fission [50] Arl-2, involved in energy homeostasis [51] mmu-miR-1a-3p chr 2 151875.1 Nd1 and Cox1, involved in OXPHOS [52] mmu-let-7f-5p chr 13 18780.3 IL-23R, related to mitochondrial respiration [53] ATP5B, involved in OXPHOS [54] mmu-let-7a-5p chr 13 16561.3 Acsl6, related to mitochondria dysfunction [55] Nd4, involved in OXPHOS [56] mmu-let-7c-5p chr 16 15125.1 nd mmu-miR-143-3p chr 18 13428.5 Bcl-2, involved in mitochondria-mediated apoptosis [57] FGF21, related to mitochondrial dysfunction [58] mmu-miR-26a-5p chr 9 11590.5 Cox5a, involved in OXPHOS [59] Creb1, Stk4, related to mitochondria dysfunction [60] mmu-let-7g-5p chr 9 9859.1 nd mmu-let-7b-5p chr 15 9291.6 PGC1alfa, related to mitochondrial respiration [61] Cytochrome b, IRS1, related to mitochondria-mediated ROS production and lipid deposition [62] mmu-miR-133a-3p chr 18 6882.9 IGF1R, related to mitochondrial stress [63] Dio3, involved in mitochondrial dysfunction [64] *…”

Human umbilical cord-derived mesenchymal stromal cells improve myocardial fibrosis and restore miRNA-133a expression in diabetic cardiomyopathy

“…Selection of candidate differentially expressed miRNAs and mRNAs from publically available sources: In order to identify miRNAs with altered expression in diabetic mouse heart, we selected Non-DM and DM group sequencing data from a miRNA high-throughput sequencing (series GSE210036 [15]) and generated a heatmap of the top 50 differentially-expressed miRNAs. From this, we selected six brosisassociated miRNAs: let-7f, miR-26a, miR-29a, miR-29b, miR-29c and miR-133a.…”

“…To identify potential candidates for DM-associated, myocardial miRNAs that may be modulated by hUC-MSC administration, we rst generated a heatmap (Fig. 5A) of the top 50 differentially expressed miRNAs in publically available datasets for cardiac tissue of groups of male C57BL/6 mice with and without STZ-induced DM for 12 weeks from the recently-published study of Cagnin et al (GSE210036, [15]). From these, 6 miRNAs were selected for quantitative (q)RT-PCR analysis in heart tissue samples from our two in vivo experiments.…”