Mechanism(s) of ischaemia/reperfusion injury and cardioprotection

Chin, K 2015, Mechanism(s) of ischaemia/reperfusion injury and cardioprotection, Doctor of Philosophy (PhD), Medical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Mechanism(s) of ischaemia/reperfusion injury and cardioprotection
Author(s) Chin, K
Year 2015
Abstract Timely myocardial reperfusion is the primary treatment for patients with acute ST-segment elevation myocardial infarction. Although this reperfusion strategy is essential for myocardial salvage, it can in itself induce myocardial damage and cardiomyocyte death, a phenomenon termed “myocardial reperfusion injury”. An emerging strategy to alleviate this ischaemia/reperfusion (I/R) injury is to manipulate the interplay between pro-injurious and pro-survival kinase pathways at the time of reperfusion.

The temporal change in the expression of pro-injurious kinases implicated during I/R, which include the mitogen-activated protein kinases (MAPKs) c-jun N-terminal kinases (JNKs) and p38 MAPK together with calcium/calmodulin-dependent protein kinase (CaMK) II and phospholamban (PLN), as well as kinases that are pro-survival including the MAPK extracellular signal-regulated kinase (Erk) 1/2, protein kinase B (Akt) and signal transducer and activator of transcription (STAT) 3. Langendorff-perfused rat hearts subjected to global ischaemia without reperfusion or followed by either 5, 15 or 30 min reperfusion were performed. Using Western blot, it was found that p38 MAPK and CaMKII were phosphorylated during ischaemia and the phosphorylation of p38 MAPK, but not CaMKII, remained elevated throughout 30 min reperfusion. No significant changes in the phosphorylation of JNK 1/2, Erk 1/2, Akt and STAT3 were observed during ischaemia while their phosphorylation was highest at 30 min of reperfusion. The phosphorylation of PLN was greatest at 5 min of reperfusion and reduced to basal levels 15 min after reperfusion.

The ability of the synthetic flavonol, 3’,4’-dihydroxyflavonol (DiOHF) to alter the expression of pro-survival and pro-injurious kinases during myocardial I/R was studied. Isolated rat hearts were subjected global ischaemia followed by 5 or 30 min reperfusion in the presence of 10 μM DiOHF. The post-ischaemic cardiac relaxation was significantly improved, accompanied by reduced cell death and apoptosis with DiOHF treatment. At 5 min reperfusion, DiOHF treatment significantly reduced the I/R-induced increased phosphorylation of PLN. At 30 min of reperfusion, I/R-induced increased phosphorylation of the pro-injurious kinase JNK 2 at 30 min of reperfusion was significantly reduced with DiOHF treatment. I/R-induced increased phosphorylation of CaMKII also tended to decrease with DiOHF treatment, although not significant, while the phosphorylation of PLN remained low with DiOHF treatment at 30 min of reperfusion.

The acute improvement in cardiac and vascular function by Angeli’s salt (AS) after myocardial I/R was investigated. The cardiac effect of AS was compared to the clinically used inotrope for acute heart failure dobutamine, while its dilator effect was compared with the nitric oxide donor, diethylamine NONOate (DEA/NO). Rat isolated hearts were subjected to normoxic perfusion or treated with I/R. Both AS and DEA/NO elicited dose-dependent increases in coronary flow in sham hearts. The vasodilator response to AS, but not DEA/NO was preserved in hearts subjected to I/R. AS and dobutamine also increased cardiac contractility in sham hearts, however positive inotropic actions caused by both AS and dobutamine were impaired in I/R-treated hearts. In addition, tachycardia caused by dobutamine, but not AS, was exacerbated in I/R-treated hearts and this may increase the risk of arrhythmias. In conclusion, these studies provide evidence to support the possible use of DiOHF and HNO in the treatment of acute myocardial infarction to reduce reperfusion injury or to improve cardiac contractility and induce vasodilatation respectively.

Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Medical Sciences
Keyword(s) 3’,4’-dihydroxyflavonol
Angeli's salt
ischaemia/reperfusion injury
cardiac contractility
signalling pathway
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Created: Wed, 23 Dec 2015, 08:34:48 EST by Denise Paciocco
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