Low-concentration of perifosine surprisingly protects cardiomyocytes from oxygen glucose deprivation

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Physiology

Background:

• Oxygen glucose deprivation (OGD)/re-oxygenation induces cardiomyocyte injury.
• Akt inhibitors are typically studied for anti-cancer effects, not cardioprotection.

Purpose of the Study:

• To investigate the unexpected protective effects of low-concentration perifosine on cardiomyocytes against OGD/re-oxygenation.
• To elucidate the molecular mechanisms underlying perifosine-mediated cardioprotection.

Main Methods:

• Utilized H9c2 cardiomyocytes and primary murine cardiomyocytes.
• Exposed cells to OGD/re-oxygenation.
• Administered non-cytotoxic concentrations of perifosine (0.1-0.5 μM).
• Assessed reactive oxygen species (ROS) production, p53 mitochondrial translocation, cyclophilin D complexation, and mitochondrial membrane potential (MMP).
• Investigated the role of AMP-activated kinase (AMPK) signaling using shRNA-knockdown and siRNA knockdown.

Main Results:

• Low-concentration perifosine suppressed OGD/re-oxygenation-induced ROS production, p53 mitochondrial translocation, cyclophilin D complexation, and MMP reduction.
• Perifosine activated AMPK signaling, leading to increased intracellular nicotinamide adenine dinucleotide phosphate (NADPH) content.
• AMPK inhibition abrogated perifosine's protective effects and NADPH production.
• Similar protective effects and AMPK activation were observed in primary murine cardiomyocytes.

Conclusions:

• Low-concentration perifosine exhibits significant cardioprotective effects against OGD/re-oxygenation injury.
• The protective mechanism involves the activation of AMPK signaling, subsequent increase in NADPH, and reduction of oxidative stress.
• Perifosine presents a novel therapeutic potential for conditions involving ischemic heart damage.