Divergent effects of miR-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microRNA targets

Samarjit Das, Mark Kohr, Brittany Dunkerly-Eyring, Dong Lee, Djahida Bedja, Oliver A. Kent, Anthony Kar Lun Leung, Jorge Henao-Mejia, Richard A. Flavell, Charles Jr Steenbergen

Research output: Contribution to journalArticle

Abstract

Background-MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR-181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results-To investigate further how the miR-181 family affects the heart, we suppressed miR-181 using a miR-181- sponge containing 10 repeated complementary miR-181 "seed" sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR-181-sponge sequence. Sponge-H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin-induced oxidative stress. We also found that miR-181a/b targets phosphatase and tensin homolog (PTEN), and the sponge-expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR-181a/b-/- and miR-181c/ d-/- knockout mice and subjected them to ischemia-reperfusion injury. Our results suggest divergent effects of different miR-181 family members: miR-181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR-181a/b-/- mice due to increased PTEN signaling, whereas miR-181c targets mt-COX1 in the mitochondria, resulting in decreased infarct size in miR-181c/d-/- mice. Conclusions-The miR-181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt-COX1 (miR-181c) or with protection by targeting PTEN (miR-181a/b).

Original languageEnglish (US)
Article numbere004694
JournalJournal of the American Heart Association
Volume6
Issue number3
DOIs
StatePublished - 2017

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MicroRNAs
Phosphoric Monoester Hydrolases
Porifera
Oxidative Stress
Gene Expression
Heart Mitochondria
Untranslated RNA
Mitochondrial Genes
Myoblasts
Reperfusion Injury
Phosphatidylinositol 3-Kinases
Knockout Mice
Cytosol
Doxorubicin
Reactive Oxygen Species
Seeds
Mitochondria
Respiration
Tensins
Cell Line

Keywords

  • MicroRNA
  • MiR-181
  • Mitochondria
  • Mitochondrial miRNA
  • Mitochondrial respiratory complex IV
  • Mt-COX1
  • Oxidative stress
  • Phosphatase and tensin homolog
  • PI3 kinase
  • Reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Divergent effects of miR-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microRNA targets. / Das, Samarjit; Kohr, Mark; Dunkerly-Eyring, Brittany; Lee, Dong; Bedja, Djahida; Kent, Oliver A.; Leung, Anthony Kar Lun; Henao-Mejia, Jorge; Flavell, Richard A.; Steenbergen, Charles Jr.

In: Journal of the American Heart Association, Vol. 6, No. 3, e004694, 2017.

Research output: Contribution to journalArticle

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abstract = "Background-MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR-181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results-To investigate further how the miR-181 family affects the heart, we suppressed miR-181 using a miR-181- sponge containing 10 repeated complementary miR-181 {"}seed{"} sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR-181-sponge sequence. Sponge-H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin-induced oxidative stress. We also found that miR-181a/b targets phosphatase and tensin homolog (PTEN), and the sponge-expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR-181a/b-/- and miR-181c/ d-/- knockout mice and subjected them to ischemia-reperfusion injury. Our results suggest divergent effects of different miR-181 family members: miR-181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR-181a/b-/- mice due to increased PTEN signaling, whereas miR-181c targets mt-COX1 in the mitochondria, resulting in decreased infarct size in miR-181c/d-/- mice. Conclusions-The miR-181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt-COX1 (miR-181c) or with protection by targeting PTEN (miR-181a/b).",
keywords = "MicroRNA, MiR-181, Mitochondria, Mitochondrial miRNA, Mitochondrial respiratory complex IV, Mt-COX1, Oxidative stress, Phosphatase and tensin homolog, PI3 kinase, Reperfusion injury",
author = "Samarjit Das and Mark Kohr and Brittany Dunkerly-Eyring and Dong Lee and Djahida Bedja and Kent, {Oliver A.} and Leung, {Anthony Kar Lun} and Jorge Henao-Mejia and Flavell, {Richard A.} and Steenbergen, {Charles Jr}",
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T1 - Divergent effects of miR-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microRNA targets

AU - Das, Samarjit

AU - Kohr, Mark

AU - Dunkerly-Eyring, Brittany

AU - Lee, Dong

AU - Bedja, Djahida

AU - Kent, Oliver A.

AU - Leung, Anthony Kar Lun

AU - Henao-Mejia, Jorge

AU - Flavell, Richard A.

AU - Steenbergen, Charles Jr

PY - 2017

Y1 - 2017

N2 - Background-MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR-181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results-To investigate further how the miR-181 family affects the heart, we suppressed miR-181 using a miR-181- sponge containing 10 repeated complementary miR-181 "seed" sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR-181-sponge sequence. Sponge-H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin-induced oxidative stress. We also found that miR-181a/b targets phosphatase and tensin homolog (PTEN), and the sponge-expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR-181a/b-/- and miR-181c/ d-/- knockout mice and subjected them to ischemia-reperfusion injury. Our results suggest divergent effects of different miR-181 family members: miR-181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR-181a/b-/- mice due to increased PTEN signaling, whereas miR-181c targets mt-COX1 in the mitochondria, resulting in decreased infarct size in miR-181c/d-/- mice. Conclusions-The miR-181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt-COX1 (miR-181c) or with protection by targeting PTEN (miR-181a/b).

AB - Background-MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR-181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results-To investigate further how the miR-181 family affects the heart, we suppressed miR-181 using a miR-181- sponge containing 10 repeated complementary miR-181 "seed" sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR-181-sponge sequence. Sponge-H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin-induced oxidative stress. We also found that miR-181a/b targets phosphatase and tensin homolog (PTEN), and the sponge-expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR-181a/b-/- and miR-181c/ d-/- knockout mice and subjected them to ischemia-reperfusion injury. Our results suggest divergent effects of different miR-181 family members: miR-181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR-181a/b-/- mice due to increased PTEN signaling, whereas miR-181c targets mt-COX1 in the mitochondria, resulting in decreased infarct size in miR-181c/d-/- mice. Conclusions-The miR-181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt-COX1 (miR-181c) or with protection by targeting PTEN (miR-181a/b).

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KW - MiR-181

KW - Mitochondria

KW - Mitochondrial miRNA

KW - Mitochondrial respiratory complex IV

KW - Mt-COX1

KW - Oxidative stress

KW - Phosphatase and tensin homolog

KW - PI3 kinase

KW - Reperfusion injury

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U2 - 10.1161/JAHA.116.004694

DO - 10.1161/JAHA.116.004694

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