Abstract
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
Highlights
Polyneuropathy including sensory neuropathy is one of the most common long-term complication of diabetes mellitus [1], which occurs in more than 50% of patients with long-standing diabetes [2]; for a review, see [3]
By using the unbiased omics approach to reveal global cardiac miRNA expression changes, we have shown the downregulation of miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, miR-34b, and an upregulation of miR-181a in the heart in a rat model of sensory neuropathy induced by systemic capsaicin treatment
We have previously found that myocardial ROS production including nitrogen monoxide (NO) and peroxynitrite levels were decreased in capsaicin-induced neuropathy model [14], which may be related to the roles of NO and peroxynitrite in myocardial ischemia or in cardiac preconditioning
Summary
Polyneuropathy including sensory neuropathy is one of the most common long-term complication of diabetes mellitus [1], which occurs in more than 50% of patients with long-standing diabetes [2]; for a review, see [3]. Capsaicin-induced sensory neuropathy has affected the expression profile of cardiac mRNAs [16]. We examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms
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