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.

Levosimendan Protects against Doxorubicin‐Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

“…Apoptosis is an active process that enables adaptation to external factors rather than a passive process, and excessive apoptosis is unfavorable. There are two relatively clear apoptotic pathways: the external pathway involves cleavage of the initiator procaspase-8 into the active caspase-8, thereby causing a series of apoptosis cascades once the Fas ligand binds to the Fas receptor on the cell surface [22,26,27]; and the endogenous pathway is strictly regulated by proteins from the Bcl-2 family and targets mitochondria, maintaining the competition between antiapoptotic Bcl-2-like survival factors and BioMed Research International proapoptotic BAX-like death factors [22,27,28]. BAX and Bcl-2 belong to the family of Bcl-2 proteins.…”

“…The ratio of those two factors determines whether apoptosis occurs, as well as the severity of apoptosis. Furthermore, as the cytokines involved in the regulation of apoptosis, caspases are core participators in the activation of apoptotic cascades [16,27,28]. The concentration of active caspase-3 is closely associated with the rate of apoptosis.…”

“…In addition, the expression of BAX and c-caspase-3 in the CON+L group was decreased. DOX activates PTEN, thereby modulating the activity downstream of the PI3K/Akt pathway [27]. PTEN mutation is the most common mutation in tumor suppressor genes which may negatively regulate cell function [29][30][31].…”

“…Regarding levosimendan, previously reported experimental results have indicated that it could increase the sensitivity between Ca 2+ and myofilaments by combining with myocardial troponin C to strengthen myocardial contraction without increasing the intracellular Ca 2+ concentration and oxygen consumption in the myocardium [13,16,27]. Simultaneously, its vasodilatory and anti-ischemic effects might be mediated by the opening of adenosine triphosphatesensitive potassium channels in vascular smooth muscle cells.…”

Multiorgan Drug Action of Levosimendan in Critical Illnesses

“…The clinical consequences of levosimendan-related tissue perfusion improvement should be evaluated taking in consideration concurrent improvement in cardiac output. In addition to its inotropic and vasodilator effects, levosimendan has several other important effects, including increase in diaphragm contractility [9, 10], anti-inflammatory effect [11–13], and antiapoptotic effect [14, 15], and affects platelet function [16–18]. In addition, levosimendan stimulated iNOS expression and nitric oxide (NO) production [19, 20].…”