High-molecular-weight polyethylene glycol protects cardiac myocytes from hypoxia- and reoxygenation-induced cell death and preserves ventricular function.

Abstract

Apoptosis plays a significant role in maladaptive remodeling and ventricular dysfunction following ischemia-reperfusion injury. There is a critical need for novel approaches to inhibit apoptotic cell death following reperfusion, as this loss of cardiac myocytes can progressively lead to heart failure. We investigated the ability and signaling mechanisms of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15-20, to protect cardiac myocytes from hypoxia-reoxygenation (H-R)-induced cell death and its efficacy in preserving ventricular function following extended hypothermic ischemia and warm reperfusion as relevant to cardiac transplantation. Pretreatment of neonatal rat ventricular myocytes with a 5% PEG solution led to a threefold decline in apoptosis after H-R relative to untreated controls. There was a similar decline in caspase-3 activity in conjunction with inhibition of cytochrome c release from the inner mitochondrial membrane. Treatment with PEG also reduced reactive oxygen species production after H-R, and sarcolemmal lipid-raft architecture was preserved, consistent with membrane stabilization. Cell survival signaling was upregulated after H-R with PEG, as demonstrated by increased phosphorylation of Akt, GSK-3β, and ERK1/2. There was also maintenance of cardiac myocyte β-adrenergic signaling, which is critical for myocardial function. PEG 15-20 was very effective in preserving left ventricular function following prolonged hypothermic ischemia and warm reperfusion. PEG 15-20 has a potent protective antiapoptotic effect in cardiac myocytes exposed to H-R injury and may represent a novel therapeutic strategy to decrease myocardial cell death and ventricular dysfunction at the time of reperfusion during acute coronary syndrome or following prolonged donor heart preservation.

• Authors: Ricky Malhotra, Vesta Valuckaite, Michelle L Staron, Tiju Theccanat, Karen M D'Souza, John C Alverdy, Shahab A Akhter
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 300 Issue 5 Pg. H1733-42 (May 2011) ISSN: 1522-1539 [Electronic] United States
• PMID: 21335476 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Polyethylene Glycols
• Caspase 3
• Oxygen

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Caspase 3 (metabolism)
• Cell Hypoxia (physiology)
• Cells, Cultured
• Membrane Microdomains (drug effects, physiology)
• Models, Animal
• Myocardial Reperfusion Injury (pathology, physiopathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects, physiology)
• Oxygen (adverse effects, pharmacology)
• Polyethylene Glycols (pharmacology)
• Rats
• Reactive Oxygen Species (metabolism)
• Ventricular Function (drug effects, physiology)