Cardiac expression of microRNA-7 is associated with adverse cardiac remodeling

Abstract

Although microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.

Hypoxia Sensing of β-Adrenergic Receptor Is Regulated by Endosomal PI3Kγ

“…16 Adult Cardiomyocyte Metabolic Labeling to Evaluate βAR Phosphorylation Metabolic labeling of primary adult cardiomyocytes was modified from our previous studies 9,14 and is detailed in Supplemental Methods. Plating medium of the adult cardiomyocytes were replaced by phosphate free MEM media containing 10 µg/mL BSA and 100 µCi/mL of [32] P-inorganic phosphate, and subjected to normoxia or hypoxia for 1.5 hours. DOB stimulation was used as positive control.…”

“…Cardiac samples were placed in fresh 4% paraformaldehyde at room temperature for 24 hours and processed through xylene exchange and embedded into paraffin blocks as described in our previous study. 19 Paraffin slides (5 µm thickness) were subsequently stained with H&E and imaged using a Slide Scanner-Aperio AT2 (Leica Biosystems).…”

The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity

“…Oxygen consumption analysis of purified mitochondria from isolated cardiomyocytes from miR-7 transgenic hearts showed significant reductions in the maximum respiration rate compared to controls, therefore confirming that overexpression of miR-7 in cardiomyocytes leads to mitochondrial dysfunction. In addition, transmission electron microscopy showed alteration in mitochondrial ultra-structures [ 54 ]. MiR-1a-3p also regulated mitochondrial oxidative phosphorylation by increasing the expression of NADH dehydrogenase subunit 1 ( ND1 ) and cytochrome c oxidase subunit 1 ( COX1 ), which are involved in the coding of complex I and complex IV of the electron transport chain.…”

Change of Heart: the Epitranscriptome of Small Non-coding RNAs in Heart Failure

“…Functional, mature microRNA transcripts are loaded onto Argonaute proteins to form an RNA-induced silencing complex (RISC), through which inhibition of translation or mRNA decay is initiated [16]. One microRNA can target multiple mRNAs, and microR-NAs can thereby regulate complex multifactorial processes, such as cardiac remodeling [17][18][19]. The important role of microRNAs in heart failure has already been extensively reviewed [20][21][22][23].…”