Elsevier

Free Radical Biology and Medicine

Volume 64, 9 September 2013, Pages 78-84
Free Radical Biology and Medicine

Review Article
Regulation of cardiac and renal ischemia–reperfusion injury by microRNAs

https://doi.org/10.1016/j.freeradbiomed.2013.06.044Get rights and content

Highlights

  • Renal and cardiac I/R injury leads to deterioration or even loss of organ function.

  • MicroRNAs are powerful regulators of gene expression and potentially of I/R injury.

  • Knowledge of microRNA deregulation in I/R injury might optimize treatment decisions.

Abstract

Tissue damage caused by ischemia–reperfusion (I/R) injury represents a serious event, which often leads to deterioration or even loss of organ function. I/R injury is associated with transient tissue oxygen deprivation due to vessel occlusion and a subsequent reperfusion period following restoration of blood flow. Initial tissue damage inflicted by ischemia is aggravated in the reperfusion period through mechanisms such as burst of reactive oxygen and nitrogen species and inflammatory reactions. I/R injury occurs during surgical interventions, organ transplantation, diseases such as myocardial infarction, circulatory shock, and toxic insults. Recently, microRNAs have come into focus as powerful regulators of gene expression and potential diagnostic tools during I/R injury. These small noncoding ribonucleotides (~22 nucleotides in length) posttranscriptionally target mRNAs, culminating in suppression of protein synthesis or increase in mRNA degradation, thus fundamentally influencing organ function. This review highlights the latest developments regarding the role of microRNAs in cardiac and renal I/R injury.

Introduction

Oxygen deprivation (ischemia) induced by transient disruption of blood supply followed by reopening of the occluded vessel (reperfusion) is a pivotal mechanism of organ injury during various medical conditions. Ischemia–reperfusion (I/R) injury is a central mechanism in myocardial infarction, circulatory shock, various toxic insults, surgical interventions, or organ transplantation; it arises after a complex cascade of events [1], [2]. During ischemia, the tissue undergoes damage that is further exacerbated by a massive burst of reactive oxygen (ROS) and nitrogen species during reperfusion [3]. The hypoxia and the following oxidative/nitrative stress result in protein modifications, lipid oxidations, and DNA breakage, triggering a chain of deleterious responses that affect all major extra- and intracellular tissue components: endothelial dysfunction, neutrophil adherence to endothelium and trans-endothelial migration, the release of inflammatory mediators, cellular calcium overload, and eventually cell death [4]. These events are the underlying mechanism of acute I/R organ damage and dysfunction in the heart and kidney.

In the “Era of Reperfusion” [5] and by use of advanced organ protection during surgery the ischemic time and associated organ damage and mortality have been significantly reduced. Although acute complications of I/R injury are still a major medical concern, the therapeutic advances led to a shift in focus on chronic complications such as organ failure. After I/R, the surviving tissue initiates an adaptive process to maintain adequate organ function, called remodeling. However, the remodeling process might eventually evolve into abnormal changes, with ensuing dysfunction and subsequent organ failure. Novel therapeutic strategies have been recently developed to target the critical event of the remodeling process. Despite the recent advances, the underlying molecular signaling between cellular components, extracellular matrix, and tissue vascularization during chronic cardiac or renal remodeling associated with I/R injury are far from being completely understood.

MicroRNAs have been implicated as transcriptional regulators in a wide range of biological processes determining cell fate, stress response, proliferation, or death [6]. The ensuing immense research effort has identified many associations between disease processes and specific microRNAs. In particular, a multitude of studies demonstrated the role of microRNAs in chronic cardiovascular or renal disease processes [7], [8], [9], [10], [11], [12].

This review provides an overview of the role of microRNAs in the development and consequences of I/R injury in the heart and kidney. Also, advances in microRNA-based biomarker and therapeutic approaches that might be important in preventing or treating I/R injury are discussed.

Section snippets

MicroRNA functions

MicroRNAs, short endogenous noncoding RNAs, are important regulators of target messenger RNA translation by binding mainly to complementary sequences of the 3′ untranslated region of target messenger RNA transcripts thereby leading to RNA degradation and/or inhibition of protein synthesis [13]. MicroRNAs are evolutionarily well conserved and are abundant in all human cells; the estimated number of microRNA genes that the human genome encodes is well above 1000, and they regulate the activity of

MicroRNAs during renal I/R injury

Targeted deletion of Dicer from the proximal tubular epithelium protects from I/R-induced renal injury (preserved renal function, less tissue damage and tubular apoptosis, survival benefit) and is associated with changes in the expression of distinct microRNAs (e.g., miR-132, -362, and -379; see Fig. 1) [17]. After unilateral warm ischemia in a murine model, nine microRNAs were shown to be differentially regulated compared to control animals (miR-21, miR-20a, miR-146a, miR-199a-3p, miR-214,

MicroRNAs during cardiac I/R injury

In recent years, several microRNAs have been implicated in the pathomechanism of cardiac I/R injury and infarction (see Fig. 2 for an overview). MiR-21 was among the top deregulated microRNAs as assessed by whole-genome microRNA profiling and validation by TaqMan quantitative real-time PCR [23]. In murine cardiac I/R injury miR-21 was specifically localized to fibroblasts in the infarct region of the heart by in situ hybridization and immunohistochemistry techniques. Phosphatase and tensin

MicroRNAs as I/R biomarkers

Cardiac biomarkers are constantly needed to refine the diagnosis and management of patients with symptoms due to acute or chronic cardiovascular or kidney diseases to facilitate early diagnosis of acute ischemic insults and risk stratification for future adverse cardiac events.

As a remarkable discovery, microRNAs have been found in the extracellular space, such as blood, urine, and other body fluids, where they are quite stable despite the existence of RNases [33]. Extracellular microRNAs were

Acknowledgments

This study was funded by the German Research Foundation (DFG-TH903/10-1 to T.T. and DFG LO-1736/1-1), the German Federal Ministry of Education and Research (IFB-Tx, BMBF 01EO0802 to T.T.), and the European Commission (FP7-PEOPLE-2011-CIG- 294278) to S.B. and T.T.

References (52)

  • K.L. Lee et al.

    Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients. GUSTO-I Investigators

    Circulation

    (1995)
  • V. Ambros

    The functions of animal microRNAs

    Nature

    (2004)
  • T. Thum et al.

    MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts

    Nature

    (2008)
  • J.M. Lorenzen et al.

    Circulating miR-210 predicts survival in critically ill patients with acute kidney injury

    Clin. J. Am. Soc. Nephrol.

    (2011)
  • E. van Rooij et al.

    A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure

    Proc. Natl. Acad. Sci. USA

    (2006)
  • T. Thum et al.

    Comparison of different miR-21 inhibitor chemistries in a cardiac disease model

    J. Clin. Invest.

    (2011)
  • J. Lorenzen et al.

    MicroRNAs in diabetes and diabetes-associated complications

    RNA Biol.

    (2012)
  • J.M. Lorenzen et al.

    Circulating and urinary microRNAs in kidney disease

    Clin. J. Am. Soc. Nephrol.

    (2012)
  • J. Fiedler et al.

    MicroRNA-24 regulates vascularity after myocardial infarction

    Circulation

    (2011)
  • R.C. Friedman et al.

    Most mammalian mRNAs are conserved targets of microRNAs

    Genome Res.

    (2009)
  • J. Bauersachs et al.

    Biogenesis and regulation of cardiovascular microRNAs

    Circ. Res.

    (2011)
  • J. Krutzfeldt et al.

    Silencing of microRNAs in vivo with 'antagomirs'

    Nature

    (2005)
  • Q. Wei et al.

    Targeted deletion of Dicer from proximal tubules protects against renal ischemia–reperfusion injury

    J. Am. Soc. Nephrol.

    (2010)
  • J.G. Godwin et al.

    Identification of a microRNA signature of renal ischemia reperfusion injury

    Proc. Natl. Acad. Sci. USA

    (2010)
  • M.D. Shapiro et al.

    MicroRNA expression data reveals a signature of kidney damage following ischemia reperfusion injury

    PLoS One

    (2011)
  • E. Aguado-Fraile et al.

    miR-127 protects proximal tubule cells against ischemia/reperfusion: identification of kinesin family member 3B as miR-127 target

    PLoS One

    (2012)
  • Cited by (57)

    • SIRT3 as a potential therapeutic target for heart failure

      2021, Pharmacological Research
      Citation Excerpt :

      Oxidative stress plays a key role in the development of experimental and clinical heart failure [52,53]. Myocardial ischemia impacts the function, morphology, and metabolism of cardiomyocytes [54–56]. Although early reperfusion is the most effective way to salvage ischemic tissues, the restoration of blood reperfusion aggravates oxidative stress in myocardial tissues, leading to cardiac dysfunction, endoplasmic reticulum stress, cell apoptosis, and myocardial fibrosis.

    • Role of nitroxyl (HNO) in cardiovascular system: From biochemistry to pharmacology

      2020, Pharmacological Research
      Citation Excerpt :

      Ischemia reperfusion injury occurs in response to insufficient blood flow and hypoxia, reperfusion of oxygenated blood may trigger tissue damage and necrosis, which often leads to deterioration or even loss of organ function [134]. HNO is implicated in renal ischemia reperfusion injury and myocardial ischemia reperfusion injury [135,136]. HNO is capable of evoking early preconditioning-protective effects in isolated rat heart [137].

    View all citing articles on Scopus
    View full text