MicroRNA Profile in Metabolic Heart Disease

Abstract

Metabolic syndrome (abdominal obesity, hyperlipidemia, hyperglycemia, insulin resistance, hypertension, systemic inflammation), usually induced by a high caloric regimen, is a pre‐requisite of type 2 diabetes, and increases the risk for cardiovascular disease. Metabolic syndrome and diabetes induce a specific cardiac phenotype known as metabolic cardiomyopathy, with an early onset as cardiac hypertrophy and diastolic dysfunction that evolves to systolic dysfunction and congestive heart failure. Normal cardiac metabolism exhibits physiologic shifts between glucose and fatty acid (FA) oxidation for ATP production. During a high caloric diet‐induced metabolic syndrome, although an excess of both glucose and FA may be present, the heart becomes almost completely reliant on FA oxidation for ATP production. Primarily driven by the large bloodstream FA availability, this metabolic inflexibility is supported by increased mitochondrial metabolism, and leads to oxidative stress, cardiac inefficiency and dysfunction. The primary molecular trigger of this energetic dysregulation is unknown. We hypothesized that the increase in mitochondrial metabolism is supported by changes in gene expression, and the latter is coordinated by alterations in microRNA expressions. Lewis rats on either a normal or high fat diet (HFD) were compared regarding cardiac structure and function, bioenergetics and gene expression profiling studies followed by validation using Illumina arrays platform and quantitative RT‐PCR. The HFD regimen caused insulin resistance, diastolic dysfunction and cardiac fibrosis. Our microarray studies have highlighted an altered miRNA expression profile in the heart upon HFD with changes in specific miRNAs that regulate insulin sensitivity, mitochondrial metabolism and cardiac pathology (hypertrophy, fibrosis, inflammation). MicroRNA 208a, which is reported to be inversely correlated with cardiac bioenergetics, was found decreased in cardiac tissue upon HFD. We identified targets of miR 208a including the cardioprotective and antioxidant factor stanniocalcin1, nuclear receptor co‐activator 7 (enhances the transcriptional activity of factors involved in mitochondrial biogenesis), mediator complex subunit 7 (regulates the activator‐induced transcription by facilitating the interaction between nuclear receptors, transcriptional co‐activator and co‐repressors, and chromatin modification factors with RNA Pol II), and sorting nexin 10 (mediates the mitochondrial‐endoplasmic reticulum lipid trafficking). Downstream targets of miR 208a, including markers of mitochondrial biogenesis and FA oxidation as well as mitochondrial oxidative phosphorylation with FA substrates, were also increased. CRISPR deletion of the miR 208a in cardiomyocytes led to a bioenergetics profile that favors mitochondrial FA metabolism. In conclusion, our data suggest a role of miR 208a in increasing mitochondrial metabolism and favoring metabolic inflexibility in the heart exposed to HFD. Cardiac metabolic rigidity and dysfunction during metabolic syndrome may be alleviated by controlling the expression of specific miRs involved in cardiac bioenergetics.Support or Funding InformationCMU Early Career Grant, AIREA Grant American Heart AssociationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.