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Myocardial infarction (MI) continues to be a major burden of disease, despite rapid reperfusion interventions. Reperfusion of ischemic hearts (reperfusion injury) induces free radical generation, activation of early stress responses and apoptosis, which contributes to ventricular remodeling and dysfunction, which may lead to developing heart failure. Mineralocorticoid receptor (MR) antagonists have been shown clinically to reduce blood pressure, particularly in resistant hypertension, and substantially increase survival in heart failure. We have previously identified a novel action of MR antagonists to prevent initiation of apoptosis during reperfusion injury by preventing degradation of anti-apoptotic repressor protein with a caspase domain (ARC). Since MR antagonists reduced the extent of infarct size (35%) below that of reperfusion alone (43%), we used expression profiling analysis to identify whether additional co-repressor and co-activator transcription factors may be activated.

Design and Method:

We used our ex-vivo model of ischemia-reperfusion (I-R), male rate hearts were exposed to ischemia for 30 min and reperfusion for 2.5hr. Following treatment, left ventricular free wall tissue was harvested from hearts that were subjected to sham I-R (n = 6), I-R alone (n = 6) and with MR antagonist, spironolactone (SPIRO, 10 nM, n = 6). Total RNA was extracted using TRIzol lysis reagent and purified using RNeasy mini kit according to manufacturers’ protocol. Microarray hybridization analysis was confirmed by qRT-PCR analysis.


Reperfusion triggered activation of additional transcriptional factors which modulate apoptosis, including c-fos, and the multifunctional molecular chaperones heat shock protein (hsp) 27 and 40. Reperfusion injury also down-regulated expression of Kruppel-like factor 15 (KLF15). SPIRO prevented I-R induced decreased KLF15 levels and downregulated c-fos, Hsp27 and Hsp40 expression.


Since KLF15 is an endogenous repressor of cardiac hypertrophy, our results suggest early administration of MR antagonists or addition to drug eluting stents for protection of the myocardium.

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