Cardioprotective and Anti-Aggregatory Effects of Levosimendan on Isoproterenol-Induced Myocardial Injury in High-Fat-Fed Rats Involves Modulation of PI3K/Akt/mTOR Signaling Pathway and Inhibition of Apoptosis: Comparison to Cilostazol

J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):456-471. doi: 10.1177/1074248418763957. Epub 2018 Apr 23.

Abstract

Hyperlipidemia and hypercoagulability states are linked with the increased risks of myocardial infarction (MI). Levosimendan has vasorelaxant and anti-aggregatory properties. The present study evaluated the anti-aggregatory and cardioprotective effects of levosimendan versus cilostazol in high-fat diet (HFD)-fed rats subjected to isoproterenol-induced MI. Rats were assigned to normal, HFD, HFD + isoproterenol, HFD + isoproterenol + cilostazol, and HFD + isoproterenol + levosimendan. The present study investigated the anti-aggregatory effect of both levosimendan and cilostazol and revealed that both drugs attenuated the severity of platelet aggregation. Moreover, both levosimendan and cilostazol revealed effectiveness in attenuating the severity of HFD/isoproterenol-induced myocardial injury as revealed by electrocardiogram signs, apoptotic markers, and histopathological score via counteracting the oxidative stress burden, increments in the expression of inflammatory mediators, and modulating nuclear factor kappa-B (NF-κB) and phosphatidylinositide 3-kinases (PI3K)/protein kinase B (Akt)/ mechanistic target of rapamycin (mTOR) pathway. It was obvious that levosimendan offered more cardioprotective properties than cilostazol. The study showed the relations between hyperlipedemia, hyperaggregability state, and myocardial injury with the modulation of NF-κB and PI3K/Akt/mTOR pathway.

Keywords: acute myocardial infarction; cilostazol; high-fat diet; levosimendan; platelet aggregation; rats.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cilostazol / pharmacology*
  • Diet, High-Fat*
  • Disease Models, Animal
  • Heart Rate / drug effects
  • Inflammation Mediators / metabolism
  • Isoproterenol*
  • Lipids / blood
  • Myocardial Infarction / chemically induced
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Signal Transduction / drug effects
  • Simendan / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Inflammation Mediators
  • Lipids
  • Platelet Aggregation Inhibitors
  • Simendan
  • mTOR protein, rat
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Isoproterenol
  • Cilostazol