Dataset Information

Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.

ABSTRACT:

Purpose of review

Insulin is at the heart of diabetes mellitus (DM). DM alters cardiac metabolism causing cardiomyopathy, ultimately leading to heart failure. Polyamines, organic compounds synthesized by cardiomyocytes, have an insulin-like activity and effect on glucose metabolism, making them metabolites of interest in the DM heart. This review sheds light on the disrupted microRNA network in the DM heart in relation to developing novel therapeutics targeting polyamine biosynthesis to prevent/mitigate diabetic cardiomyopathy.

Recent findings

Polyamines prevent DM-induced upregulation of glucose and ketone body levels similar to insulin. Polyamines also enhance mitochondrial respiration and thereby regulate all major metabolic pathways. Non-coding microRNAs regulate a majority of the biological pathways in our body by modulating gene expression via mRNA degradation or translational repression. However, the role of miRNA in polyamine biosynthesis in the DM heart remains unclear. This review discusses the regulation of polyamine synthesis and metabolism, and its impact on cardiac metabolism and circulating levels of glucose, insulin, and ketone bodies. We provide insights on potential roles of polyamines in diabetic cardiomyopathy and putative miRNAs that could regulate polyamine biosynthesis in the DM heart. Future studies will unravel the regulatory roles these miRNAs play in polyamine biosynthesis and will open new doors in the prevention/treatment of adverse cardiac remodeling in diabetic cardiomyopathy.

SUBMITTER: Kambis TN

PROVIDER: S-EPMC8668854 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.

Kambis Tyler N TN Tofilau Hadassha M N HMN Gawargi Flobater I FI Chandra Surabhi S Mishra Paras K PK

Current diabetes reports 20211213 12

<h4>Purpose of review</h4>Insulin is at the heart of diabetes mellitus (DM). DM alters cardiac metabolism causing cardiomyopathy, ultimately leading to heart failure. Polyamines, organic compounds synthesized by cardiomyocytes, have an insulin-like activity and effect on glucose metabolism, making them metabolites of interest in the DM heart. This review sheds light on the disrupted microRNA network in the DM heart in relation to developing novel therapeutics targeting polyamine biosynthesis to ...[more]

PMID: 34902085

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Project description:Background:Hyper-free fatty acidemia (HFFA) impairs cardiac capillaries, as well as type 2 diabetes mellitus (T2DM). Perilipin 5 (Plin5) maintains metabolic balance of free fatty acids (FFAs) in high oxidative tissues via the states of nonphosphorylation and phosphorylation. However, when facing to T2DM-HFFA, Plin5's role in cardiac microvascular endothelial cells (CMECs) is not defined. Methods:In mice of WT or Plin5-/-, T2DM models were rendered by high-fat diet combined with intraperitoneal injection of streptozocin. CMECs isolated from left ventricles were incubated with high glucose (HG) and high FFAs (HFFAs). Plin5 phosphorylation was stimulated by isoproterenol. Plin5 expression was knocked down by small interfering RNA (siRNA). We determined cardiac function by small animal ultrasound, apoptotic rate by flow cytometry, microvessel quantity by immunohistochemistry, microvascular integrity by scanning electron microscopy, intracellular FFAs by spectrophotometry, lipid droplets (LDs) by Nile red staining, mRNAs by quantitative real-time polymerase chain reaction, proteins by western blots, nitric oxide (NO) and reactive oxygen species (ROS) by fluorescent dye staining and enzyme-linked immunosorbent assay kits. Results:In CMECs, HFFAs aggravated cell injury induced by HG and activated Plin5 expression. In mice with T2DM-HFFA, Plin5 deficiency reduced number of cardiac capillaries, worsened structural incompleteness, and enhanced diastolic dysfunction. Moreover, in CMECs treated with HG-HFFAs, both ablation and phosphorylation of Plin5 reduced LDs content, increased intracellular FFAs, stimulated mitochondrial β-oxidation, added ROS generation, and reduced the expression and activity of endothelial nitric oxide synthase (eNOS), eventually leading to increased apoptotic rate and decreased NO content, all of which were reversed by N-acetyl-L-cysteine. Conclusion:Plin5 preserves lipid balance and cell survival in diabetic CMECs by regulating FFAs metabolism bidirectionally via the states of nonphosphorylation and phosphorylation.

Project description:BackgroundThe PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.MethodsTo focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.ResultsUpon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.ConclusionCAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.

Dataset Information

Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.

Purpose of review

Recent findings

Publications

Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.

Similar Datasets

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