DIFFERENTIAL CHANGES IN CARDIAC PHOSPHOLAMBAN AND SARCOPLASMIC RETICULAR CA2+-ATPASE PROTEIN-LEVELS - EFFECTS ON CA2+ TRANSPORT AND MECHANICS IN COMPENSATED PRESSURE-OVERLOAD HYPERTROPHY AND CONGESTIVE-HEART-FAILURE

The objective of this study was to elucidate the role of the sarcoplasmic reticulum (SR) in the transition from compensated pressure-overload hypertrophy (increased left ventricular [LV] mass, normal LV function, and no pulmonary congestion) to congestive heart failure (increased LV mass, depressed LV function, and pulmonary congestion). To address this issue, the descending thoracic aorta was banded for 4 and 8 weeks in adult guinea pigs, and the changes in isovolumic LV mechanics, SR Ca2+ transport, and SR protein levels were determined and compared with age-matched sham-operated control animals. A subgroup of the 8-week banded animals manifested the congestive heart failure phenotype with diminished developed LV pressure normalized by LV mass, reduced rates of LV pressure development and relaxation, and markedly increased lung weight-to-body weight ratios. The cardiac mechanical and morphometric changes were associated with depressed protein levels of the SR Ca2+-ATPase (85% of the control) and phospholamban (65% of the control) assessed by quantitative immunoblotting. Resultant rates of SR Ca2+ uptake (V-max) and the affinity of SR Ca2+-ATPase for Ca2+ (EC(50)) were significantly depressed [32 +/- 6 nmol Ca2+. min(-1). mg(-1) and 0.59 +/- 0.12 (mu mol/L)/L, respectively] compared with the 8-week sham-operated control animals [40 +/- 1 nmol Ca2+. min(-1). mg(-1) and 0.40 +/- 0.05 (mu mol/L)/L, respectively]. We conclude that this model of pressure overload-induced cardiac failure is associated with (1) diminished LV force development, rates of pressure development, and decay; (2) depressed protein expression of the Ca2+-cycling, proteins SR Ca2+-ATPase and phospholamban; and (3) decreased V-max and affinity of the SR Ca2+-ATPase for Ca2+. These findings implicate these Ca2+-cycling proteins in the pathogenesis of congestive heart failure.