Growth/death, Regeneration and Stem cellsP276Early alterations of sarcoplasmic reticulum calcium uptake and apoptosis towards improving cell survival after acute myocardial ischemia/reperfusion

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Abstract

Purpose

Apoptosis is the main determination of cell death after early acute cardiac ischemia/reperfusion (AMI/R). We evaluated the effects of AMI/R on SR Ca-cycling (Serca2, Pln) and survival/apoptotic proteins (Hax1, activated cleaved caspase-3, Bax, and Bcl2).

Methods

Male Wistar rats were subjected to left coronary artery ligation and allowed to recover for 48 hours and 2 weeks post-surgery, while sham-operated animals served as controls. Whole cell extracts were obtained from cardiac tissue, and protein expression levels were determined by western blot analysis using Gapdh as internal control.

Results

At 48h post-surgery, left ventricular ejection fraction (EF%) was 69.0 ± 1.1 % in SHAM and 41.6 ± 0.9 % in AMI/R, p < 0.05. At 2 weeks post-surgery, EF% was 76.0 ± 2.0 % in SHAM vs 48.7 ± 1.9 % in AMI/R, p < 0.05. An early increase of Serca2 (29%) protein expression was observed while PLN levels remained unaltered. This indicates an increase in both the maximal velocity and the affinity of the SR Ca-transport system. However, the Hax1 levels were also increased (68%), which could promote the formation of PLN monomers and inhibition of Serca2. The activated cleaved caspase-3 levels were increased by 26% while the Bcl2/Bax ratio remained unchanged. Hax1 overexpression may be an important compensatory response against apoptosis (as seen by the increased caspase-3). Furthermore, two weeks post AMI/R, although Serca2, Hax1 and Pln levels were similar to controls, the activated caspase-3 was reduced by 36% and the Bcl2/Bax ratio was increased by 56%, indicating a different phase of cardiac remodeling.

Conclusions

Early increase of Serca2 under maintained PLN levels may reflect the need for improved SR Ca-transport in the infarcted and reperfused myocardium. The early compensation of apoptosis by Hax1 at the cost of SR Ca transport activity may also be critical for ischemic myocardial survival.

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