Dataset Information

Substantial Dysregulation of miRNA Passenger Strands Underlies the Vascular Response to Injury.

ABSTRACT: Vascular smooth muscle cell (VSMC) dedifferentiation is a common feature of vascular disorders leading to pro-migratory and proliferative phenotypes, a process induced through growth factor and cytokine signaling cascades. Recently, many studies have demonstrated that small non-coding RNAs (miRNAs) can induce phenotypic effects on VSMCs in response to vessel injury. However, most studies have focused on the contribution of individual miRNAs. Our study aimed to conduct a detailed and unbiased analysis of both guide and passenger miRNA expression in vascular cells in vitro and disease models in vivo. We analyzed 100 miRNA stem loops by TaqMan Low Density Array (TLDA) from primary VSMCs in vitro. Intriguingly, we found that a larger proportion of the passenger strands was significantly dysregulated compared to the guide strands after exposure to pathological stimuli, such as platelet-derived growth factor (PDGF) and IL-1α. Similar findings were observed in response to injury in porcine vein grafts and stent models in vivo. In these studies, we reveal that the miRNA passenger strands are predominantly dysregulated in response to vascular injury.

SUBMITTER: Pinel K

PROVIDER: S-EPMC6406808 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Substantial Dysregulation of miRNA Passenger Strands Underlies the Vascular Response to Injury.

Pinel Karine K Diver Louise A LA White Katie K McDonald Robert A RA Baker Andrew H AH

Cells 20190123 2

Vascular smooth muscle cell (VSMC) dedifferentiation is a common feature of vascular disorders leading to pro-migratory and proliferative phenotypes, a process induced through growth factor and cytokine signaling cascades. Recently, many studies have demonstrated that small non-coding RNAs (miRNAs) can induce phenotypic effects on VSMCs in response to vessel injury. However, most studies have focused on the contribution of individual miRNAs. Our study aimed to conduct a detailed and unbiased ana ...[more]

PMID: 30678104

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Project description:Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).

Dataset Information

Substantial Dysregulation of miRNA Passenger Strands Underlies the Vascular Response to Injury.

Publications

Substantial Dysregulation of miRNA Passenger Strands Underlies the Vascular Response to Injury.

Similar Datasets

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