Related Experiment Videos
Regional alterations in SR Ca(2+)-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium
J A Fallavollita1, S Jacob, R F Young
1Department of Veterans Affairs, Western New York Health Care System, Buffalo, New York 14214, USA.
Insights
Chronic heart dysfunction in hibernating myocardium is linked to sarcoplasmic reticulum (SR) protein changes. This study reveals molecular alterations in SR proteins, suggesting reversible ischemia as an early defect in left ventricular dysfunction.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Hibernating myocardium is a state of chronic left ventricular dysfunction.
- Understanding the molecular mechanisms underlying this dysfunction is crucial for therapeutic development.
Purpose of the Study:
- To investigate the molecular mechanisms responsible for chronic dysfunction in hibernating myocardium.
- To explore the role of sarcoplasmic reticulum (SR) protein expression in this condition.
Main Methods:
- Pigs underwent left anterior descending artery stenosis to induce hibernating myocardium.
- Angiography assessed myocardial function and perfusion.
- Northern and Western blot analyses quantified mRNA and protein levels of SR proteins (phospholamban, SR Ca(2+)-ATPase, calsequestrin) and heat shock protein 70 (HSP-70).
Main Results:
- Hibernating myocardium exhibited severe hypokinesis, reduced subendocardial perfusion, and critically low adenosine flow.
- Histology showed no evidence of myocardial necrosis.
- Regional downregulation of phospholamban and SR Ca(2+)-ATPase mRNA and protein was observed in hibernating myocardium.
- Upregulation of HSP-70 mRNA was detected in hibernating myocardium.
Conclusions:
- Hibernating myocardium displays a molecular phenotype similar to end-stage ischemic cardiomyopathy.
- Sarcoplasmic reticulum (SR) dysfunction, stemming from reversible ischemia, may represent an early defect in the progression of left ventricular dysfunction.
Abstract:
We sought to identify mechanisms for chronic dysfunction in hibernating myocardium. Pigs were instrumented with a left anterior descending artery stenosis for 3 mo. Angiography demonstrated high-grade stenoses and hibernating myocardium with 1) severe anterior hypokinesis (P < 0.001 vs. shams), 2) reduced subendocardial perfusion [0.73 +/- 0.05 (SE) vs. 1.01 +/- 0.06 ml. min(-1). g(-1) in normal, P < 0.001], and 3) critically reduced adenosine flow (1.0 +/- 0.17 vs. 3.84 +/- 0.26 ml. min(-1). g(-1) in normal, P < 0.001). Histology did not reveal necrosis. Northern blot analysis of hibernating myocardium demonstrated regional downregulation in mRNAs for sarcoplasmic reticulum (SR) proteins phospholamban (0.76 +/- 0.08 vs. 1.07 +/- 0.06, P < 0.02) and SR Ca(2+)-ATPase (0.83 +/- 0.06 vs. 1.02 +/- 0.06, P < 0.05) with no change in calsequestrin (1.08 +/- 0.06 vs. 0.96 +/- 0.05, P = not significant). Heat shock protein (HSP)-70 mRNA was regionally induced in hibernating myocardium (2.4 +/- 0.3 vs. 1.0 +/- 0.11, P < 0.01). Directionally similar changes were confirmed by Western blot analysis of respective proteins. Our results indicate that hibernating myocardium exhibits a molecular phenotype that on a regional basis is similar to end-stage ischemic cardiomyopathy. This supports the hypothesis that SR dysfunction from reversible ischemia may be an early defect in the progression of left ventricular dysfunction.