DOWN-REGULATION OF SARCOPLASMIC-RETICULUM CA2-ATPASE DURING PROGRESSION OF LEFT-VENTRICULAR HYPERTROPHY()

To determine whether reduced sarcoplasmic reticulum (SR) Ca2+-adenosin etriphosphatase (ATPase) (SERCA2) activity contributes to delayed myoc ardial relaxation during chronic left ventricular hypertrophy (LVH) pr ogression, LVH was produced in rats by abdominal aortic coarctation. S ystolic and diastolic functions were assessed in vivo 8 and 16 wk afte r surgery, and compositional alterations in LV myocardium [SERCA2 conc entration, myosin heavy chain (MHC) isoenzymes, and tissue collagen] w ere correlated with the development of prolonged isovolumic relaxation and impaired cardiac performance over time. Myocardial relaxation was prolonged in 8-wk banded rats, despite normal isovolumic systolic fun ction and LV end-diastolic pressure (LVEDP). No significant alteration s in SERCA2 protein, beta-MHC, or fibrillar collagen levels were obser ved at this early time point. In contrast, LV SERCA2, beta-MHC, and fi brillar collagen concentrations were all significantly altered in 16-w k banded rats. These late compositional changes were associated with r educed cardiac performance, as manifested by a significant elevation i n LVEDP (14 +/- 2 mmHg). The 34% decrease in SERCA2 protein was associ ated with reduced SR Ca2+ uptake and an even greater reduction (76%) i n SERCA2 mRNA. SERCA2 mRNA levels were also significantly reduced to 4 3 +/- 10% of sham-operated rats 8 wk after banding, despite unchanged SERCA2 protein levels and normal SR Ca2+ uptake. These results argue a gainst a significant contribution of SERCA2 downregulation to the subt le alterations in myocardial relaxation observed in compensated LVH. H owever, the early reduction in SERCA2 mRNA levels may serve as a molec ular marker for impaired cardiac performance during the transition fro m compensated LVH to heart failure.