Review ArticleRegulation of cardiac and renal ischemia–reperfusion injury by microRNAs
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.
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