Levosimendan Pretreatment Inhibits Myocardial Apoptosis in Swine after Coronary Microembolization

Abstract

Background/Aims: In addition to its cardiotonic effect, levosimendan has been thought to have multiple cardiovascular benefits, including anti-inflammatory and anti-apoptotic. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been revealed to be up-regulated in circumstances of coronary microembolization (CME), and the PTEN signaling pathway mediates myocardial apoptosis in swine after CME. However, whether this functional protein could be modified by pretreatment of levosimendan in models of CME has not been disclosed yet. Methods: Swine CME was induced by intra-coronary injection of inertia plastic microspheres (diameter 42µm) into left anterior descending coronary, with or without pretreatment of levosimendan or PTEN siRNA. Echocardiologic measurements, Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining and western blotting were applied to assess their functional, morphological and molecular effects in CME. Results: PTEN mRNA and protein were aberrantly up-regulated in cardiomyocytes following CME. Furthermore, down-regulation of PTEN in vivo via siRNA was associated with an improved cardiac function, attenuated myocardial apoptosis, and concomitantly inhibited expressions of key proapoptotic proteins such as caspase-3. Interestingly, levosimendan could markedly attenuate PTEN expression and inhibit myocardial apoptosis, therefore partially reverse cardiac dysfunction. Conclusion: Modulation of PTEN was probably as a potential mechanism involved in the beneficial effects of pretreatment of levosimendan to cardiac function and apoptosis in animal models of CME.