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

We sought to identify mechanisms for chronic dysfunction in hibernating myo cardium. Pigs were instrumented with a left anterior descending artery sten osis for 3 mo. Angiography demonstrated high-grade stenoses and hibernating myocardium with 1) severe anterior hypokinesis (P < 0.001 vs. shams), 2) r educed subendocardial perfusion [0.73 +/- 0.05 (SE) vs. 1.01 +/- 0.06 ml.mi n(-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). Hi stology did not reveal necrosis. Northern blot analysis of hibernating myoc ardium demonstrated regional downregulation in mRNAs for sarcoplasmic retic ulum (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 ch ange 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 m yocardium (2.4 +/- 0.3 vs. 1.0 +/- 0.11, P < 0.01). Directionally similar c hanges 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 m ay be an early defect in the progression of left ventricular dysfunction.