Regulation of cardiac expression of the diabetic marker microRNA miR-29.

Diabetes mellitus (DM) is an independent risk factor for heart disease and its underlying mechanisms are unclear. Increased expression of diabetic marker miR-29 family miRNAs (miR-29a, b and c) that suppress the pro-survival protein Myeloid Cell Leukemia 1(MCL-1) is reported in pancreatic β-cells in...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nicholas Arnold, Purushotham Reddy Koppula, Rukhsana Gul, Christian Luck, Lakshmi Pulakat
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/51db6bdb22d543d68aef43e545bf6412
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:51db6bdb22d543d68aef43e545bf6412
record_format	dspace
spelling	oai:doaj.org-article:51db6bdb22d543d68aef43e545bf64122021-11-25T06:07:04ZRegulation of cardiac expression of the diabetic marker microRNA miR-29.1932-620310.1371/journal.pone.0103284https://doaj.org/article/51db6bdb22d543d68aef43e545bf64122014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25062042/?tool=EBIhttps://doaj.org/toc/1932-6203Diabetes mellitus (DM) is an independent risk factor for heart disease and its underlying mechanisms are unclear. Increased expression of diabetic marker miR-29 family miRNAs (miR-29a, b and c) that suppress the pro-survival protein Myeloid Cell Leukemia 1(MCL-1) is reported in pancreatic β-cells in Type 1 DM. Whether an up-regulation of miR-29 family miRNAs and suppression of MCL-1 (dysregulation of miR-29-MCL-1 axis) occurs in diabetic heart is not known. This study tested the hypothesis that insulin regulates cardiac miR-29-MCL-1 axis and its dysregulation correlates with DM progression. In vitro studies with mouse cardiomyocyte HL-1 cells showed that insulin suppressed the expression of miR-29a, b and c and increased MCL-1 mRNA. Conversely, Rapamycin (Rap), a drug implicated in the new onset DM, increased the expression of miR-29a, b and c and suppressed MCL-1 and this effect was reversed by transfection with miR-29 inhibitors. Rap inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling in HL-1 cells. Moreover, inhibition of either mTORC1 substrate S6K1 by PF-4708671, or eIF4E-induced translation by 4E1RCat suppressed MCL-1. We used Zucker diabetic fatty (ZDF) rat, a rodent model for DM, to test whether dysregulation of cardiac miR-29-MCL-1 axis correlates with DM progression. 11-week old ZDF rats exhibited significantly increased body weight, plasma glucose, insulin, cholesterol, triglycerides, body fat, heart weight, and decreased lean muscle mass compared to age-matched lean rats. Rap treatment (1.2 mg/kg/day, from 9-weeks to 15-weeks) significantly reduced plasma insulin, body weight and heart weight, and severely dysregulated cardiac miR-29-MCL1 axis in ZDF rats. Importantly, dysregulation of cardiac miR-29-MCL-1 axis in ZDF rat heart correlated with cardiac structural damage (disorganization or loss of myofibril bundles). We conclude that insulin and mTORC1 regulate cardiac miR-29-MCL-1 axis and its dysregulation caused by reduced insulin and mTORC1 inhibition increases the vulnerability of a diabetic heart to structural damage.Nicholas ArnoldPurushotham Reddy KoppulaRukhsana GulChristian LuckLakshmi PulakatPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e103284 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicholas Arnold Purushotham Reddy Koppula Rukhsana Gul Christian Luck Lakshmi Pulakat Regulation of cardiac expression of the diabetic marker microRNA miR-29.
description	Diabetes mellitus (DM) is an independent risk factor for heart disease and its underlying mechanisms are unclear. Increased expression of diabetic marker miR-29 family miRNAs (miR-29a, b and c) that suppress the pro-survival protein Myeloid Cell Leukemia 1(MCL-1) is reported in pancreatic β-cells in Type 1 DM. Whether an up-regulation of miR-29 family miRNAs and suppression of MCL-1 (dysregulation of miR-29-MCL-1 axis) occurs in diabetic heart is not known. This study tested the hypothesis that insulin regulates cardiac miR-29-MCL-1 axis and its dysregulation correlates with DM progression. In vitro studies with mouse cardiomyocyte HL-1 cells showed that insulin suppressed the expression of miR-29a, b and c and increased MCL-1 mRNA. Conversely, Rapamycin (Rap), a drug implicated in the new onset DM, increased the expression of miR-29a, b and c and suppressed MCL-1 and this effect was reversed by transfection with miR-29 inhibitors. Rap inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling in HL-1 cells. Moreover, inhibition of either mTORC1 substrate S6K1 by PF-4708671, or eIF4E-induced translation by 4E1RCat suppressed MCL-1. We used Zucker diabetic fatty (ZDF) rat, a rodent model for DM, to test whether dysregulation of cardiac miR-29-MCL-1 axis correlates with DM progression. 11-week old ZDF rats exhibited significantly increased body weight, plasma glucose, insulin, cholesterol, triglycerides, body fat, heart weight, and decreased lean muscle mass compared to age-matched lean rats. Rap treatment (1.2 mg/kg/day, from 9-weeks to 15-weeks) significantly reduced plasma insulin, body weight and heart weight, and severely dysregulated cardiac miR-29-MCL1 axis in ZDF rats. Importantly, dysregulation of cardiac miR-29-MCL-1 axis in ZDF rat heart correlated with cardiac structural damage (disorganization or loss of myofibril bundles). We conclude that insulin and mTORC1 regulate cardiac miR-29-MCL-1 axis and its dysregulation caused by reduced insulin and mTORC1 inhibition increases the vulnerability of a diabetic heart to structural damage.
format	article
author	Nicholas Arnold Purushotham Reddy Koppula Rukhsana Gul Christian Luck Lakshmi Pulakat
author_facet	Nicholas Arnold Purushotham Reddy Koppula Rukhsana Gul Christian Luck Lakshmi Pulakat
author_sort	Nicholas Arnold
title	Regulation of cardiac expression of the diabetic marker microRNA miR-29.
title_short	Regulation of cardiac expression of the diabetic marker microRNA miR-29.
title_full	Regulation of cardiac expression of the diabetic marker microRNA miR-29.
title_fullStr	Regulation of cardiac expression of the diabetic marker microRNA miR-29.
title_full_unstemmed	Regulation of cardiac expression of the diabetic marker microRNA miR-29.
title_sort	regulation of cardiac expression of the diabetic marker microrna mir-29.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/51db6bdb22d543d68aef43e545bf6412
work_keys_str_mv	AT nicholasarnold regulationofcardiacexpressionofthediabeticmarkermicrornamir29 AT purushothamreddykoppula regulationofcardiacexpressionofthediabeticmarkermicrornamir29 AT rukhsanagul regulationofcardiacexpressionofthediabeticmarkermicrornamir29 AT christianluck regulationofcardiacexpressionofthediabeticmarkermicrornamir29 AT lakshmipulakat regulationofcardiacexpressionofthediabeticmarkermicrornamir29
_version_	1718414161821564928

Regulation of cardiac expression of the diabetic marker microRNA miR-29.

Ejemplares similares