Regional alterations in SR Ca2+-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium

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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−1in normal, P < 0.001], and 3) critically reduced adenosine flow (1.0 ± 0.17 vs. 3.84 ± 0.26 ml ⋅ min−1⋅ g−1in 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 Ca2+-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.

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