Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1

doi:10.1016/j.bbrc.2008.09.025

Biochemical and Biophysical Research Communications

Volume 376, Issue 3, 21 November 2008, Pages 548-552

https://doi.org/10.1016/j.bbrc.2008.09.025 Get rights and content

Abstract

Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The present study investigated whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9C2 through microRNA regulated insulin-like growth factor (IGF-1) signaling pathway. Our data showed that H9C2 cells exposed to high glucose have increased miR-1 expression level, decreased mitochondrial membrane potential, increased cytochrome-c release, and increased apoptosis. Glucose induced mitochondrial dysfunction, cytochrome-c release and apoptosis was blocked by IGF-1. Using prediction algorithms, we identified 3′-untranslated regions of IGF-1 gene are the target of miR-1. miR-1 mimics, but not mutant miR-1, blocked the capacity of IGF-1 to prevent glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis. In conclusion, our data demonstrate that IGF-1 inhibits glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis and IGF-1’s effect is regulated by miR-1.

Section snippets

Materials and methods

Cellcultureandreagents. The rat cardiomyocyte cell line H9C2 was purchased from ATCC (Manassas, VA), and cultured in DMEM. The cultures were supplemental with 10% fetal bovine serum and 100 μg/ml penicillin/streptomycin. IGF-1 was obtained from GroPep (Australia), and glucose was obtained from Sigma.

QuantificationoffragmentedDNAincelldeathbyELISA. DNA fragmentation in cell death was analyzed using a cell death detection ELISA kit (Roche) according to the manufacturer’s instructions. To determine

Glucose exposure induces apoptotic cell death in H9C2

H9C2 exposed to glucose underwent apoptotic death in a manner dependent upon incubation time and concentrations of glucose. Analysis of histone-associated DNA fragments showed that incubation of the cells with 25 mM glucose caused a concentration- and time-dependent DNA fragmentation and cell loss in the cultures over the 96 h interval (Fig. 1A). Significant cell death occurred in the cultures exposed to glucose at 25 mM for 96 h. The untreated H9C2 showed little changes in DNA fragmentation and

Discussion

In the present study, we demonstrated that the effects of IGF-1 on preventing glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis are mediated by miR-1. To our knowledge, these novel findings have not been reported before.

Our findings that glucose increased miR-1 expression are consistent with previous reports that the increased expression of miR-1 was found in the ventricular samples from diabetic patients [29]. Our studies that miR-1 mimics rather than mutant miR-1

Acknowledgments

This work was supported by American Heart Association (0765149Y to Y. Li), MacDonald Foundation (07RDM008 to Y. Li), and National Natural Science Foundation of China (30772142, 30571850 to X. Yu).

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¹: These authors contributed equally to this work.

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Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1

Abstract

Section snippets

Materials and methods

Glucose exposure induces apoptotic cell death in H9C2

Discussion

Acknowledgments

Eur. J. Pharmacol.

Biochim. Biophys. Acta

Cell

Neuron

Cell

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene

Circ. Res.

Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor

Circulation

Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology

Proc. Natl. Acad. Sci. USA

Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species

Cardiovasc. Res.

High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms

Diabetes

Effect of the antioxidant α-lipoic acid on apoptosis in human umbilical vein endothelial cells induced by high glucose

Clin. Exp. Med.

Up-regulation of plasma membrane-associated redox activities in neuronal cells lacking functional mitochondria

J. Neurochem.

Mitochondrial oxidative stress. Physiologic consequences and potential for a role in aging

Ann. N.Y. Acad. Sci.

Mitochondrial oxidative stress, DNA damage, and heart failure

Antioxid. Redox Signal.