Inhibition of miR-15 protects against cardiac ischemic injury

Thomas G. Hullinger, Rusty L. Montgomery, Anita G. Seto, Brent A. Dickinson, Hillary M. Semus, Joshua M. Lynch, Christina M. Dalby, Kathryn Robinson, Christianna Stack, Paul A. Latimer, Joshua Hare, Eric N. Olson, Eva Van Rooij

Research output: Contribution to journalArticle

294 Citations (Scopus)

Abstract

Rationale: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. Objective: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Methods and Results: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. Conclusions: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.

Original languageEnglish
Pages (from-to)71-81
Number of pages11
JournalCirculation Research
Volume110
Issue number1
DOIs
StatePublished - Jan 6 2012

Fingerprint

MicroRNAs
Wounds and Injuries
Myocardial Infarction
Swine
Cardiac Myocytes
Heart Injuries
Small Untranslated RNA
Reperfusion Injury
Oligonucleotides
Inhibition (Psychology)
Regeneration
Cause of Death
Heart Diseases
Cell Death
Therapeutics
Gene Expression
locked nucleic acid

Keywords

  • anti-miR therapy
  • ischemia reperfusion
  • microRNA
  • miR-15 family

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hullinger, T. G., Montgomery, R. L., Seto, A. G., Dickinson, B. A., Semus, H. M., Lynch, J. M., ... Van Rooij, E. (2012). Inhibition of miR-15 protects against cardiac ischemic injury. Circulation Research, 110(1), 71-81. https://doi.org/10.1161/CIRCRESAHA.111.244442

Inhibition of miR-15 protects against cardiac ischemic injury. / Hullinger, Thomas G.; Montgomery, Rusty L.; Seto, Anita G.; Dickinson, Brent A.; Semus, Hillary M.; Lynch, Joshua M.; Dalby, Christina M.; Robinson, Kathryn; Stack, Christianna; Latimer, Paul A.; Hare, Joshua; Olson, Eric N.; Van Rooij, Eva.

In: Circulation Research, Vol. 110, No. 1, 06.01.2012, p. 71-81.

Research output: Contribution to journalArticle

Hullinger, TG, Montgomery, RL, Seto, AG, Dickinson, BA, Semus, HM, Lynch, JM, Dalby, CM, Robinson, K, Stack, C, Latimer, PA, Hare, J, Olson, EN & Van Rooij, E 2012, 'Inhibition of miR-15 protects against cardiac ischemic injury', Circulation Research, vol. 110, no. 1, pp. 71-81. https://doi.org/10.1161/CIRCRESAHA.111.244442
Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circulation Research. 2012 Jan 6;110(1):71-81. https://doi.org/10.1161/CIRCRESAHA.111.244442
Hullinger, Thomas G. ; Montgomery, Rusty L. ; Seto, Anita G. ; Dickinson, Brent A. ; Semus, Hillary M. ; Lynch, Joshua M. ; Dalby, Christina M. ; Robinson, Kathryn ; Stack, Christianna ; Latimer, Paul A. ; Hare, Joshua ; Olson, Eric N. ; Van Rooij, Eva. / Inhibition of miR-15 protects against cardiac ischemic injury. In: Circulation Research. 2012 ; Vol. 110, No. 1. pp. 71-81.
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abstract = "Rationale: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. Objective: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Methods and Results: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. Conclusions: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.",
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AU - Lynch, Joshua M.

AU - Dalby, Christina M.

AU - Robinson, Kathryn

AU - Stack, Christianna

AU - Latimer, Paul A.

AU - Hare, Joshua

AU - Olson, Eric N.

AU - Van Rooij, Eva

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N2 - Rationale: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. Objective: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Methods and Results: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. Conclusions: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.

AB - Rationale: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. Objective: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Methods and Results: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. Conclusions: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.

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