Pharmacological Inhibition of PTEN Restores Remote Ischemic Postconditioning Cardioprotection in Hypercholesterolemic Mice: Potential Role of PTEN/AKT/GSK3β SIGNALS.

Abstract

Although remote ischemic postconditioning (RIPC) was shown to confer cardioprotection against myocardial ischemia/reperfusion (I/R) injury in normal animals, whether RIPC-induced cardioprotection is altered in the presence of hypercholesterolemia, a comorbidity with acute myocardial infarction (AMI) patients has yet to be determined. Normal or 2% cholesterol chow was fed to male C57BL/6J mice for 12 weeks to induce hypercholesterolemia, then normal or hypercholesterolemic murine hearts were exposed to AMI by coronary artery ligation. RIPC was induced by four episodes of 5 min femoral artery occlusion followed by 5 min reperfusion immediately after myocardial reperfusion in mice. Following I/R, RIPC significantly attenuated postischemic infarct size, hindered cardiomyocyte apoptosis, improved cardiac systolic function, decreased phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, and further increased Akt and GSK-3β phosphorylation in non-hypercholesterolemic, but not in hypercholesterolemic mice. Application of the PTEN inhibitor bisperoxovanadium (BpV) (1.0 mg/kg) reduced postischemic infarct size, attenuated cardiomyocyte apoptosis, and improved cardiac dysfunction in normal, but not in hypercholesterolemic mice. Further, increased dose of BpV (2 mg/kg or 10 mg/kg) failed to rescue the detrimental effects of hypercholesterolemia on I/R in mice following I/R. Especially important, we demonstrated that the combination BpV and RIPC exerted marked cardioprotective effects both in normal and hypercholesterolemic mice with I/R, indicating that PTEN inhibition restores RIPC-elicited myocardial protection in the presence of hypercholesterolemia. Our results demonstrated that hypercholesterolemia attenuated RIPC-induced cardioprotection against I/R injury by alteration of PTEN/Akt/GSK3β signals, and inhibition of PTEN rescued RIPC-induced cardioprotection in the presence of hypercholesterolemia.

• Authors: Jun Hong, Hong-Wei Ge, Jing-Quan Liu, Ren-Hua Sun, Fei-Juan Kong
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 52 Issue 5 Pg. 522-531 (11 2019) ISSN: 1540-0514 [Electronic] United States
• PMID: 30499878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vanadium Compounds
• bisperoxovanadium
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• Glycogen Synthase Kinase 3 beta (metabolism)
• Hypercholesterolemia (drug therapy, metabolism, pathology)
• Ischemic Postconditioning
• Male
• Mice
• PTEN Phosphohydrolase (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Vanadium Compounds (pharmacology)